阅读说明：本技术 用于监测样品中激酶活性的方法 (Method for monitoring kinase activity in a sample ) 是由 阿德里安斯·弗雷德里克·马尔滕·奥尔特拉尔 蒂埃里·托马斯·施米德林 于 2019-06-21 设计创作，主要内容包括：本发明涉及监测样品中激酶活性或活化的方法,该方法包括以下步骤：a)提供包含激酶的样品,b)将样品与蛋白酶一起温育以将步骤a)中提供的激酶裂解为蛋白酶特异性蛋白水解肽,c)对样品应用磷酸肽富集,d)通过液相色谱-质谱法分析步骤c)中获得的样品,以及e)检测步骤a)中提供的激酶的磷酸化,其中,仅在鉴定出与激酶活化区域相关的蛋白水解肽的情况下才执行步骤e)的检测。(The present invention relates to a method of monitoring kinase activity or activation in a sample, the method comprising the steps of: a) providing a sample comprising a kinase, b) incubating the sample with a protease to cleave the kinase provided in step a) into protease-specific proteolytic peptides, c) applying phosphopeptide enrichment to the sample, d) analyzing the sample obtained in step c) by liquid chromatography-mass spectrometry, and e) detecting phosphorylation of the kinase provided in step a), wherein the detection of step e) is performed only if a proteolytic peptide associated with the kinase activation region is identified.)

1. A method for monitoring kinase activity or activation in a sample, the method comprising the steps of:

a) providing a sample comprising a kinase;

b) incubating the sample with a protease to cleave the kinase provided in step a) into protease-specific proteolytic peptides;

c) performing phosphopeptide enrichment on the sample;

d) analyzing the sample obtained in step c) by liquid chromatography-mass spectrometry; and

e) detecting phosphorylation of the kinase provided in step a),

wherein the detection of step e) is performed only if a proteolytic peptide associated with the activation region of the kinase is identified.

2. The method of claim 1, wherein the method further comprises the steps of:

i) determining the kinase to be monitored;

ii) determining protease-specific proteolytic peptides associated with the activation region of the kinase of interest; and

iii) adjusting the settings of the mass spectrometer so that in step e) only the protease-specific proteolytic peptides determined in step ii) are detected.

3. The method according to claim 1 or 2, wherein the method further comprises the steps of:

f) quantifying the phosphorylation detected in step e).

4. A method according to claim 3, wherein, in step f), quantification is achieved by targeted mass spectrometry.

5. The method of claim 3 or 4, wherein in step f), quantification is by targeting MS1, MS2, or MS basedⁿWherein n is an integer greater than 2.

6. The method of any one of the preceding claims, wherein the proteolytic peptide associated with the activation region of the kinase comprises a proteolytic peptide associated with the t-loop of the kinase.

7. The method according to any one of the preceding claims, wherein the protease is selected from trypsin, endoprotease Glu-C, chymotrypsin and endoprotease Asp-N.

8. The method according to any of the preceding claims, wherein the phosphopeptide enrichment is selected from immobilized metal ion affinity chromatography (IMAC) such as Fe (III) -IMAC, Ga (III) -IMAC, Ti (IV) -IMAC or Zr (IV) -IMAC, and Metal Oxide Affinity Chromatography (MOAC) such as TiO (MoC)₂-MOAC or ZrO₂-MOAC。

9. The method of any one of the preceding claims, wherein the phosphopeptide enrichment comprises fe (iii) -IMAC.

10. The method of any one of the preceding claims, wherein the liquid chromatography comprises reverse phase chromatography.

11. The method of any one of the preceding claims, wherein the liquid chromatography is selected from the group consisting of nano-liquid chromatography, capillary flow liquid chromatography and capillary micro-flow liquid chromatography.

12. The method of any preceding claim, wherein the mass spectrometry comprises a mass spectrometry acquisition method selected from: selective reaction monitoring, multiple reaction monitoring, parallel reaction monitoring, and high resolution multiple reaction monitoring.

13. The method of any preceding claim, wherein the mass spectrometry comprises a mass spectrometry acquisition method selected from: mass spectrometry based on Data Independent Acquisition (DIA) and targeted peptide quantitation.

14. The method of any one of the preceding claims, wherein said mass spectrometry comprises tandem mass spectrometry.

15. The method of any preceding claim, wherein the mass spectrometry comprises using a quadrupole mass spectrometer or a time-of-flight mass spectrometer.

16. A method according to any preceding claim, wherein the mass spectrometry comprises using an ion trap mass spectrometer, such as an orbitrap mass spectrometer or a linear ion trap mass spectrometer.

17. The method according to any of the preceding claims, wherein in step d) the liquid chromatography-mass spectrometry comprises using nano liquid chromatography in combination with MS/MS in selective reaction monitoring mode on a triple quadrupole mass spectrometer.

Detailed Description

The present invention relates to methods for monitoring kinase activity in a sample.

Protein kinases play a key role in cellular communication, and aberrant kinase activity has been linked to a variety of diseases ranging from cancer to diabetes or cardiovascular disease. Kinases are key regulators of cellular communication, and inhibitors thereof play a central role in targeted therapy and precision medicine. Therefore, studies on systemic kinase kinetics (global kinase dynamics) are crucial to understanding cellular function and driving rational drug development. This clear kinase correlation has led to numerous efforts to assess the activity status of the protein kinase panel. However, most of them have substantial drawbacks.

In the first applications, kinase activity was extracted from their abundance obtained in shotgun (shotgun) proteomics experiments. To address the low abundance of most protein kinases, kinase-specific enrichment protocols have been used, consisting mainly of immobilized, broad-spectrum specific kinase inhibitors and/or ATP mimics. This approach provides significant kinase enrichment, but at the expense of sensitivity, requires large input materials, limiting the approach to cell line-based model systems. Importantly, the assessment of kinase abundance does not reflect kinase activity per se, and to date, kinase activity has been mainly extracted from phosphoproteomic data. Here, alignments of over-or under-represented (over-or under-represented) sequence motifs in phosphorylated proteomic data sets are correlated with known kinase consensus sequences. However, there is a large gap in the cognition of this approach, as most of the detected phosphorylation sites (phosphosites) have not been characterized in terms of function and the substrate specificity for many kinases is redundant or not known at all.

In view of the above, there is an urgent need to directly monitor kinase activity, which has so far been mainly extracted from kinase protein expression levels or substrate phosphorylation data.

The invention thus provides a method for monitoring kinase activity or activation in a sample, the method comprising the steps of:

a) providing a sample comprising a kinase;

b) incubating the sample with a protease to cleave the kinase provided in step a) into protease-specific proteolytic peptides;

c) performing phosphopeptide enrichment on the sample;

d) analyzing the sample obtained in step c) by liquid chromatography-mass spectrometry (LC-MS); and

e) detecting phosphorylation of the kinase provided in step a),

wherein the detection of step e) is performed only if a proteolytic peptide associated with the activation region of the kinase is identified.

In order to identify and detect proteolytic peptides associated with the kinase activation region, the method of the invention comprises the steps of:

i) determining the kinase to be monitored;

ii) determining protease-specific proteolytic peptides associated with the activation region of the kinase of interest; and

iii) adjusting the settings of the mass spectrometer so that in step e) only the protease-specific proteolytic peptides determined in step ii) are detected. It is noteworthy that in the incubation step b) of the method of the invention, the incubation of the sample with one protease will produce a protease-specific proteolytic peptide associated with the activation region of the kinase of interest which is different compared to the case where another protease is used. As a result, the protease-specific proteolytic peptide determined in step ii) may vary based on the protease used. Thus, the choice of protease will also lead to a different set-up of the mass spectrometer in step iii) in order to detect only proteolytic peptides associated with the activated region of the kinase. In other words, the mass spectrometer is used to identify (selectively select) only those proteolytic peptides of interest, i.e. proteolytic peptides associated with the activation region of the kinase of interest. In addition, it should be noted that the number of protease-specific proteolytic peptides determined may vary. In one aspect, a plurality of protease-specific proteolytic peptides are determined in order to detect any activity or activation of the kinase of interest. On the other hand, a highly selective subset (subset) of protease-specific proteolytic peptides is determined in order to detect only the specific relevant activity or activation of the kinase of interest, e.g. to detect specific proteolytic peptides associated with the signaling pathway of a certain disease. It should also be noted that the determination of protease-specific proteolytic peptides in step ii) may lead to a reference list for adjusting the mass spectrometer settings. In other words, the identification (selective selection) of the protease-specific proteolytic peptide of interest is based on the reference list generated in step ii). It should also be noted that the determination of the proteolytic peptide of interest is based on the binding of the kinase of interest (i.e. the kinase to be monitored) to the protease used in the incubation step.

It has been found that by providing the method of the invention, a direct correlation between phosphorylation site abundance and kinase activity can now be achieved. The activation region in kinases is a flexible loop located near the catalytic loop that, when phosphorylated, activates most kinases. The activation region in kinases is also considered to be the t-loop and the region immediately following the activation loop, called the P +1 loop, containing a conserved region flanked by Asp-Phe-gly (dfg) and (Ala) -Pro-Glu ((a) PE) motifs. Note that the term "conserved region", "conserved domain" or "activation region" of the kinase is a term well known in the kinase art. For example, the National Center for Biotechnology Information (NCBI) provides a variety of tools (e.g., via a conserved domain database) to identify and determine the activation regions of a variety of kinases. Based on the information provided by such databases, the inventors were able to identify 456 activation regions in kinases.

By providing the method of the present invention, it is now possible to monitor the phosphorylation associated with the activation region in kinases, such as t-loop phosphorylation, which is a key switch for the initiation of activity in many of these kinases. It is noteworthy that the function of these sites can be directly transferred to many of the kinases under study (understuded) based on their high degree of sequence similarity. It has been found that phosphorylation associated with the activation region, particularly t-loop phosphorylation, is notoriously inadequate in prior art methods (e.g., shotgun proteome analysis) due to its low abundance, unfavorable properties for LC-MS, and high incidence of tyrosine phosphorylation.

The method of the present invention may further comprise the steps of:

f) quantifying the phosphorylation detected in step e).

Preferably, the quantification is by targeted mass spectrometry such as based on targeted MS1 (precursor ion scan), MS2 (tandem mass spectrometry or fragment ion scan) or MS2ⁿ(tandem mass spectrometry) in which the MS is treatedⁿAnd n is an integer greater than 2.

In a preferred embodiment, the proteolytic peptide associated with the activation region of the kinase comprises a proteolytic peptide associated with the t-loop of the kinase. By performing the detection of step e) only if a proteolytic peptide associated with the t-loop of the kinase is identified, kinase activity or activation can be monitored without further re-processing of the sample prior to applying the method of the invention. As already indicated, the proteolytic peptide associated with the activation region varies depending on the protease used. In one embodiment of the invention, the protease may be selected from trypsin, endoprotease Glu-C, chymotrypsin and endoprotease Asp-N, thereby producing a trypsin-specific proteolytic peptide (e.g., a trypsin peptide), a Glu-C specific proteolytic peptide, a chymotrypsin-specific proteolytic peptide (e.g., a chymotrypsin peptide) and an Asp-N specific proteolytic peptide, respectively. However, other proteases known to those skilled in the art may also be selected when carrying out the method of the present invention.

The phosphopeptide enrichment is preferably selected from the group consisting of immobilized metal ion affinity chromatography (IMAC) such as Fe (III) -IMAC, Ga (III) -IMAC, Ti (IV) -IMAC or Zr (IV) -IMAC, and Metal Oxide Affinity Chromatography (MOAC) such as TiO (TiO)₂-MOAC or ZrO₂-MOAC, etc. In a most preferred embodiment, the t-cyclic phosphopeptide enrichment comprises Fe (III) -IMAC. It has been found that the use of fe (iii) -IMAC will result in a process with high specificity, in particular for t-loop phosphorylation.

In another preferred embodiment, the liquid chromatography may comprise reverse phase chromatography and may be selected from the group consisting of nano-liquid chromatography, capillary flow liquid chromatography and capillary micro-flow liquid chromatography. And the mass spectrometry algorithm may comprise a mass spectrometry acquisition method selected from the group consisting of: selective Reaction Monitoring (SRM), Multiple Reaction Monitoring (MRM), Parallel Reaction Monitoring (PRM), and high resolution multiple reaction monitoring (MRM-HR). Even further, the mass spectrometry acquisition method may be selected from mass spectrometry based on data-independent acquisition (DIA or SWATH)^TM) And targeting peptide quantitation (e.g., QuanDirect)^TM). Note that the choice of mass spectrometry acquisition method depends on the available mass spectrometer. It has been found that any of the above-described mass spectrometry methods, i.e. targeted mass spectrometry methods, can be selected for carrying out the method of the invention. Even further, mass spectrometry can include tandem mass spectrometry. Preferably, mass spectrometry comprises the use of a quadrupole mass spectrometer, for example a triple quadrupole mass spectrometer, or a time-of-flight mass spectrometer. Moreover, mass spectrometry can include the use of an ion trap mass spectrometer, such as an orbitrap mass spectrometer, or a linear ion trap mass spectrometer. It has been found that by combining nano-LC with MS/MS in an SRM mode on a triple quadrupole mass spectrometer, monitoring a broad t-loop phosphorylation within the system to indicate kinase activity, can provide a highly specific approach.

Based on the methods of the present invention, assays for t-loop phosphorylation of 178 protein kinases are provided, accounting for approximately 33% of the global group of human kinases (kinemes). The advantage of this technique is the combination of sensitivity (t-cyclic phosphopeptide enrichment and LC-MS) to flux, which enables substantial kinase group coverage even starting from limited starting materials (kineme coverage). Such high sensitivity coverage can be facilitated by using (automated) platforms with parallel phosphopeptide enrichment of up to 96 samples. In a number of cell types (primary and patient-derived), 74 t-loop phosphorylation of 58 kinases were detected in total. The targeted kinases include a variety of clinically relevant kinases with FDA approved inhibitors such as MET, ABL, SRC, BTK, JAK3 and KIT (see also: fig. 1A and 1B). Table 1 provides a complete summary of the t-loop phosphorylation detected in various cell lines. Figure 6 provides a complete list of tryptic peptides.

Table 1 list of t-loop phosphorylation detected in various cell lines.

Further enhancement of kinase panel coverage (kineme coverage) may be provided by application of other proteases, sample fractionation or enrichment of specific cellular compartments such as the nucleus or cell membrane.

Experiment of

The basal kinase activity status (basal kinase activity state) was analyzed for three different cell lines, Jurkat, PC9 and Hek, without any form of stimulation. This resulted in the detection of 52 t-loop phosphorylation sites on three cell lines (fig. 2A). Due to the high degree of conservation of the kinase t loop sequence, representative tryptic peptides are not always unique. This leads to a degree of uncertainty, for example for the kinase family members Mark1, Mark2, Mark3 and Mark4, or extremely related kinases such as tyrosine kinases FYN, YES1 and SRC which often exhibit redundant functions. To resolve this uncertainty, the principles of protein classification were followed, and these examples were referred to as kinase groups throughout the study. For the 52 phosphorylation sites observed, this resulted in 48 kinase panels. Furthermore, although the t-loop is well defined by the flanking DFG and (a) PE motifs, phosphorylation can still occur at a variety of different or even multiple residues. Although the activating residues are clearly identified for many kinases, these sites within the t-loop are unknown for other kinases. Thus, for unknown situations, a number of possibilities are considered, which lead to the development of SRM assays for various phosphorylation site (phosphosite) isomers.

A large proportion of the 48 kinase panels examined represent typical housekeeping kinases that are critical to cell growth under typical culture conditions, such as CDK and MAPK, as well as the two highly abundant kinases PDK1 and GSK 3. In addition, several kinases involved in anti-apoptotic processes, such as HIPK3, were detected in the active state. Both Jurkat cells and PC9 cells showed enhanced Ca compared to Hek cells²⁺DAG-dependent signal transduction activity, while several kinases from the CaMK class and PKC family were detected in their active state. These include CaMK1D, PKC θ, and the kinase sets PKC α/PKC β/PKC γ. On the other hand, CaMKIV activity was detected only in Jurkat cells.

Interestingly, many kinases show a cell line-dependent spectrum of activity. Some of these are known to be expressed in a tissue-specific manner, such as the tyrosine kinase ZAP70 is expressed only in certain cell types (including T cells) associated with the immune system. Thus, t-loop phosphorylation of ZAP70 was only detected in Jurkat cells.

Other tyrosine kinases such as FAK, MET and the two kinase groups EPHA3/4/5 and HCK/LYN were not detectable in Jurkat cells, but they showed high activity especially in PC9 cells. This indicates an increase in tyrosine kinase activity in PC9, which may be due to activated EGFR signaling. Notably, these active phosphorylations occur at tyrosine residues in the t-loop sequence, which control primary activation of a number of kinases (primary activation). In particular, tyrosine kinases and MAP kinases require tyrosine phosphorylation in their t-loops to achieve full activation, while the primary activation site of most other kinases is a threonine residue.

Tyrosine phosphorylation is naturally under-represented in phosphoproteomic analysis unless specific enrichment of phosphorylated tyrosine is performed beforehand. It has been found that a considerable recovery of tyrosine t-loop phosphorylation is achieved by Fe (III) -IMAC phosphopeptide enrichment in combination with sensitive SRM analysis.

For FAK and MET, localization information of phosphorylation sites within the t-loop was obtained for measurement in PC 9.

After successful detection of several t-loop phosphorylations in unstimulated cells, the method was further fine-tuned to reveal activation of specific kinases from a steady-state background under selected stimuli, since a large fraction of the kinase group (kinemes) exist in an unactivated (unphosphorylated) state. Jurkat cells were treated with TNF α for 8 hours, resulting in increased cell death. Following TNF α stimulation, the receptor-interacting protein serine-threonine kinase (RIPK) is recruited to the TNF receptor complex and mediates apoptosis (fig. 2B). Following TNF α treatment, RIPK1 phosphorylation at serine S161 was reproducibly detected, and no phosphorylation was detected in untreated Jurkat cells (fig. 2C).

Although RIPK1 has a well-known role in cell death, it was found that t-loop phosphorylation of RIPK1 could be detected directly from cell lysates by the methods of the invention using MS. Thus, the RIPK1 assay provides a novel comprehensive readout to monitor the complex regulation of cell death, while also demonstrating the unparalleled sensitivity of our technique.

Assays developed based on the methods of the invention include a total of 51 peptide sequences present in various positional isomers. Of these 41 exist in 2 different subtypes (isofom), and 10 exist in 3 different subtypes. Although it is generally believed that most of the phosphorylation site localization isomers (phosphosites localization isomers) are indistinguishable by chromatographic retention time on reversed phase LC, baseline chromatographic separation was shown for all positional isomers of 47 of 51 sequences using the method of the present invention. An example of three phosphorylation sites of the kinase DDR2 is shown in fig. 3A. The other two peptide sequences show partial chromatographic separation, which enables a clear distinction of different phosphorylation site locations in complex samples by using specific conversion of the phosphorylation site locations. One example is tyrosine phosphorylation of residues Y980 and Y981 of JAK3 shown in figure 3B.

The sensitivity of the kinase activity profiling method was explored by in-depth analysis of kinase array kinetics (kineme dynamics) from primary cells (primary cells). The technique of the present invention was used to study the mechanism of platelet activation. Platelets activated by hexapeptides mimicking thrombin, which bind to the protease activated receptor 1(PAR1) for 1 minute and 5 minutes, were analyzed, and the kinase activity profile of these platelets was compared to the initial profilePlatelets were compared. By using only 300 μ g protein input per phosphopeptide enrichment, 31 t-loop phosphorylations in the 25 kinase panel could be detected and quantified. Comparative quantification analysis between activated platelets and initial platelets showed that there was a dramatic change in kinase group activity (kinase activity) levels following activation with PAR 1.

Fig. 4A depicts the quantitative differences in volcano plots (volcano plots) for 1 minute and 5 minute activation, respectively. Platelet activation involves various intracellular signaling events, most of which converge into a common pathway as shown in fig. 4B. Of note here are t-loop phosphorylation assays in two Tec families of tyrosine kinases, Btk and Tec, both of which are associated with platelet activation. In particular, Btk's role as a primary activator of PLC γ 2 is well recognized, whereas Tec's, for example, in the case of X-linked agammaglobulinemia, are associated with a more compensatory role in the absence or abnormality of Btk. The kinase activity profile presented herein demonstrates these important roles of Btk and Tec in platelet activation.

Interestingly, the degree of kinase activation and kinetics were found to be different for the two Tec family kinases. Btk activity increased almost 4-fold after 1 minute of Par1 activation and remained increased at 5 minutes, Tec showed much lower activation and also did not increase later, confirming the dominant effect of Btk (fig. 4C).

Downstream, one central convergence point after PAR1 stimulation is the activation of phospholipase c (plc), which leads to intracellular Ca²⁺Thereby increasing the activity of calcium/calmodulin dependent kinase (CaMK). It was found that the activation state of CaMK2 could be monitored by quantifying two adjacent phosphorylation sites in the T-loop (T305 and T306, fig. 4D). Both phosphorylation sites showed a significant peak 1 min after PAR1 activation and a significant drop 5 min later, indicating a shorter time involved in kinase activation. Interestingly, the specific kinetics of the two phosphorylation sites are slightly different. Although T306 phosphorylation increased more than 10-fold after 1 minute and returned to near baseline after 5 minutes, the intensity of the T305 spike was much lower, but decayed more slowly, suggesting a dynamic modulation of both phosphorylation events occurring in the T-loop of CaMK 2.

Another target of PLC activity is PKC, which in turn activates p 38. It has been found that several t-loop phosphorylations of PKC family members, including redundant t-loop sequences of PKC δ, PKC θ and PKC α, PKC β and PKC γ, can now be quantified. Interestingly, none of them showed any significant difference, whereas the downstream target p38A was changed very sharply. P38A required dual phosphorylation at T179 and Y181 to achieve full kinase activity, a state that was particularly evident after 1 min of Par1 activation, and declined dramatically after 5 min (fig. 4E). In parallel, p38A, mono-phosphorylated at Y181, remained at baseline after 1 min and only increased slightly after 5 min, suggesting that slow, partial dephosphorylation occurred after fast dual phosphorylation of p38A, resulting in an observed up-regulation of phosphorylation of single Y181 after 5 min, consistent with previous studies. Combining the observed t-loop phosphorylation of PKC with t-loop phosphorylation of p38 indicates that: the very rapid spike in PKC activity disappeared in less than 1 minute, but it was able to further activate p38 downstream; or the peak signal of p38 activation (masssif signal) was amplified compared to the PKC activity level.

Increasing intracellular Ca²⁺Another well studied effect of the levels is activation of the RAS via its transport to the plasma membrane and subsequent activation of the MAPK cascade pathway. The role of the MAPK cascade pathway in platelets has not been fully elucidated, since platelets are anucleate cells with no potential for growth, differentiation or proliferation, however, it appears to be maintaining elevated intracellular Ca²⁺The relevant factor of the level. Increased kinase activity is shown for specific members of the MAPK signaling cascade. A slight increase in RAF activity was observed after 1 minute of Par1 activation, resulting in strong activation of Erk1 and Erk2 (FIG. 4F). Finally, several t-loop phosphorylation of kinases that function in other platelet activation pathways, such as Fyn, Lyn, Yes, MKK4, JNK2, and FAK2, were observed, but no substantial difference in phosphorylation was observed, indicating the presence of baseline activity (baseline activity).

After an efficient analysis of kinase activation in primary cells, the usefulness of the method of the invention for studying an imbalance in kinase activity in diseases was explored. Kinases have become a major drug target class, especially in cancer, 25 kinase-targeted drugs have been approved and many drug candidates are in clinical evaluation. However, in distinguishing these candidates by synthetic lethal screening (synthetic lethality screen), the (long-term) inhibitory effect of one kinase on the rest of the kinase group (kineme) is usually ignored. This always leads to treatment resistance (treatment resistance) against targeted kinase inhibition due to the adaptation of the signal transduction network.

To demonstrate the potential of the method of the invention, acquired resistance in melanoma was investigated. Most melanomas are driven by the mutation of BRAFV600E, which results in constitutive activity of BRAF. Despite initial success, treatment of patients with BRAF inhibitors (BRAFi) often results in rapid acquisition of acquired resistance. Here, t-loop phosphorylation in an untreated, treatment-sensitive and drug-resistant tumor state, matched patient-derived melanoma cell line formed from patient-derived xenografts was studied (fig. 5A), where the acquired resistance was based on the NRASQ61K mutation.

By comparing the differences in kinase group activity in all three states, 39 phosphorylation sites were detected and quantified, thus representing t-loop phosphorylation in the 36 kinase groups (FIGS. 5B-5D).

Several of the quantified kinases showed increased activity in resistant cell lines compared to untreated and treatment sensitive cells. These kinases include CaMKIV, several members of the PKC kinase family such as PKC δ, PKC μ/v, several members associated with the MAPK cascade such as p38A, Erk2, Erk4 and MKK4, as well as the MAPK-responsive kinase NLK and cell cycle-related kinases CDK2/3 and Chk 2. Surprisingly, several kinases that are specifically activated in drug resistant cell lines are primarily associated with tumor suppressor activity, such as Chk2, p38A, and Erk 4.

The strongest activation was observed for the kinase Erk4, which together with Erk3, where this was also observed, belongs to the atypical MAPK family due to its lack of a tyrosine domain in the activation loop. MK5 is by far the only known substrate for Erk3 and Erk 4. MK5 is mainly thought to have tumor suppressor functions, such as activating p53 and FOXO 3. However, recent studies have also shown the oncogenic potential of the Erk3/Erk4/MK5 group, e.g., by inhibiting JNK activity and supporting angiogenesis. In addition, increased MK5 mRNA expression correlates with an increased probability of developing tumor metastases.

Interestingly, the kinetics of ERK3/ERK4 expression was linked to increased expression of both BRAFV600E and oncogenic RAS, which resulted in increased expression of ERK3 and ERK4, respectively. The data show that inhibition of BRAFV600E occurs simultaneously with decreased t-loop phosphorylation of Erk3, which is accompanied by a decrease in MK5 (fig. 5E). The levels of Erk3 were restored after acquired resistance and, strikingly, oncogenic RAS dramatically increased phosphorylation of the Erk4 t loop by more than 20-fold compared to naive and sensitive cells. Overall, this results in higher MK5 kinase activity in drug-resistant cells compared to untreated cells. The results indicate that the ERK3/ERK4/MK5 system may have an interesting role in the NRAS driven BRAFi resistance (BRAFi resistance) in melanoma and highlight the potential of the methods of the invention in detecting altered kinase panel activity by targeted tumor therapy.

Sequence listing

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1 5 10

<210> 12

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> HCK (Y411), Lyn (Y397)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 12

Val Ile Glu Asp Asn Glu Tyr Thr Ala Arg

1 5 10

<210> 13

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Araf (T454), Braf (T599), C-Raf/Raf1 (T491)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 13

Ile Gly Asp Phe Gly Leu Ala Thr Val Lys

1 5 10

<210> 14

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ICK (T157), MAK (T157)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 14

Pro Pro Tyr Thr Asp Tyr Val Ser Thr Arg

1 5 10

<210> 15

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ICK (T157/Y159), MAK (T157/Y159)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 15

Pro Pro Tyr Thr Asp Tyr Val Ser Thr Arg

1 5 10

<210> 16

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ICK (Y159), MAK (Y159)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 16

Pro Pro Tyr Thr Asp Tyr Val Ser Thr Arg

1 5 10

<210> 17

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11A (S577), CDK11B (S589)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 17

Glu Tyr Gly Ser Pro Leu Lys

1 5

<210> 18

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKAα (T198), PKAβ (T198), PKAγ (T198)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 18

Thr Trp Thr Leu Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Ile Ile

1 5 10 15

Leu Ser Lys

<210> 19

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKAα (T202), PKAβ (T202), PKAγ (T202)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 19

Thr Trp Thr Leu Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Ile Ile

1 5 10 15

Leu Ser Lys

<210> 20

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Tie1 (Y1007), GCN2 (Y70)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 20

Gly Glu Glu Val Tyr Val Lys

1 5

<210> 21

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> VGFR2 (Y1059), VGFR3 (Y1068)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 21

Asp Pro Asp Tyr Val Arg

1 5

<210> 22

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MEK1 (S218), MEK2 (S222)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 14

<223> phosphorylation

<400> 22

Leu Cys Asp Phe Gly Val Ser Gly Gln Leu Ile Asp Ser Met Ala Asn

1 5 10 15

Ser Phe Val Gly Thr Arg

20

<210> 23

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (T392), Abl2/Arg (T438)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 23

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 24

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (T392), Abl2/Arg (T438)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 24

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 25

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (Y393), Abl2/Arg (Y439)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 25

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 26

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (Y393), Abl2/Arg (Y439)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 26

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 27

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (T394), Abl2/Arg (T440)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 27

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 28

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Abl (T394), Abl2/Arg (T440)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 28

Leu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys

1 5 10

<210> 29

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GSK3A (Y279), GSK3B (Y216)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 29

Gly Glu Pro Asn Val Ser Tyr Ile Cys Ser Arg

1 5 10

<210> 30

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RSK1/p90RSK (T573), RSK2 (T577)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 30

Ala Glu Asn Gly Leu Leu Met Thr Pro Cys Tyr Thr Ala Asn Phe Val

1 5 10 15

Ala Pro Glu Val Leu Lys

20

<210> 31

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RSK1/p90RSK (T573), RSK2 (T577)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 31

Ala Glu Asn Gly Leu Leu Met Thr Pro Cys Tyr Thr Ala Asn Phe Val

1 5 10 15

Ala Pro Glu Val Leu Lys

20

<210> 32

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (T183), JNK3 (T221)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 32

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 33

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (T183/Y185), JNK3 (T221/Y223)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 33

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 34

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (T183/Y185), JNK3 (T221/Y223)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 34

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 35

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (T183), JNK3 (T221)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 35

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 36

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (Y185), JNK3 (Y223)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 36

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 37

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK1 (Y185), JNK3 (Y223)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 37

Thr Ala Gly Thr Ser Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 38

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA3 (Y779), EphA4 (Y779), EphA5 (Y833)

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 38

Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Arg

1 5 10

<210> 39

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K10 (S262), M3K9 (S308)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 39

Met Ser Ala Ala Gly Thr Tyr Ala Trp Met Ala Pro Glu Val Ile Arg

1 5 10 15

<210> 40

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K10 (T266), M3K9 (T312)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 40

Met Ser Ala Ala Gly Thr Tyr Ala Trp Met Ala Pro Glu Val Ile Arg

1 5 10 15

<210> 41

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK2 (T160), CDK3 (T160)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 41

Thr Tyr Thr His Glu Val Val Thr Leu Trp Tyr Arg

1 5 10

<210> 42

<211> 17

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PAK1 (T427), PAK2 (T406), PAK3 (T440)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 42

Ser Thr Met Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Val Val Thr

1 5 10 15

Arg

<210> 43

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T305), KCC2B (T306), KCC2D (T306)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 43

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 44

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T305/T306), KCC2B (T306/T307), KCC2D (T306/T307)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 44

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 45

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T305/T306), KCC2B (T306/T307), KCC2D (T306/T307)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 45

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 46

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T305), KCC2B (T306), KCC2D (T306)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 46

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 47

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T306), KCC2B (T307), KCC2D T307)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 47

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 48

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC2A (T306), KCC2B (T307), KCC2D T307)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 48

Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg

1 5 10

<210> 49

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkB (Y702), TrkC (Y705)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 49

Asp Val Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 50

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkB (Y706), TrkC (Y709)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 50

Asp Val Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 51

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkB (Y707), TrkC (Y710)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 51

Asp Val Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 52

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> TTN (Y8490), [TBRG1 (Y234)]

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 52

Tyr Thr Cys Gln Ile Lys

1 5

<210> 53

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DMPK (S216), MRCKA (S222), MRCKB (S221)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 53

Leu Ala Asp Phe Gly Ser Cys Leu Lys

1 5

<210> 54

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PDK1 (S241), PDK2 (S241)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 54

Ala Asn Ser Phe Val Gly Thr Ala Gln Tyr Val Ser Pro Glu Leu Leu

1 5 10 15

Thr Glu Lys

<210> 55

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MARK1 (T215), MARK2 (T208), MARK3 (T211), MARK4 (T214)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 55

Leu Asp Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala Pro Glu Leu Phe

1 5 10 15

Gln Gly Lys

<210> 56

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MARK1 (T215/S219), MARK2 (T208/S212), MARK3 (T211/S215), MARK4

(T214/S218)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 56

Leu Asp Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala Pro Glu Leu Phe

1 5 10 15

Gln Gly Lys

<210> 57

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MARK1 (S219), MARK2 (S212), MARK3 (S215), MARK4 (S218)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 57

Leu Asp Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala Pro Glu Leu Phe

1 5 10 15

Gln Gly Lys

<210> 58

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK3 (Y980), PKR2 (Y113), PKR1 (Y122)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 58

Asp Tyr Tyr Val Val Arg

1 5

<210> 59

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK3 (Y980/Y981), PKR2 (Y113/Y114), PKR1 (Y122/Y123)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 59

Asp Tyr Tyr Val Val Arg

1 5

<210> 60

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK3 (Y981), PKR2 (Y114), PKR1 (Y123)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 60

Asp Tyr Tyr Val Val Arg

1 5

<210> 61

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DYRK2 (Y382), DYRK4 (Y264)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 61

Val Tyr Thr Tyr Ile Gln Ser Arg

1 5

<210> 62

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DYRK2 (T381/Y382), DYRK4 (T263/Y264)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 62

Val Tyr Thr Tyr Ile Gln Ser Arg

1 5

<210> 63

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DYRK2 (Y382), DYRK4 (Y264)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 63

Val Tyr Thr Tyr Ile Gln Ser Arg

1 5

<210> 64

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PAK6 (S560), PAK7 (S602)

<400> 64

Ser Leu Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Val Ile Ser Arg

1 5 10 15

<210> 65

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PAK6 (S560), PAK7 (S602)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 65

Ser Leu Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Val Ile Ser Arg

1 5 10 15

<210> 66

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Dyr1A (S310), Dyr1B (S262)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 66

Ile Val Asp Phe Gly Ser Ser Cys Gln Leu Gly Gln Arg

1 5 10

<210> 67

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Dyr1A (Y319/Y321), Dyr1B (Y271/Y273)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 67

Ile Tyr Gln Tyr Ile Gln Ser Arg

1 5

<210> 68

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Dyr1A (Y321), Dyr1B Y273)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 68

Ile Tyr Gln Tyr Ile Gln Ser Arg

1 5

<210> 69

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK9 (S175)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 69

Ala Phe Ser Leu Ala Lys

1 5

<210> 70

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ZAP70 (Y492)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 70

Ala Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg

1 5 10

<210> 71

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (Y234)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 71

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 72

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (Y234/S235)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 72

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 73

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (Y234/S235)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 73

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 74

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (Y234)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 74

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 75

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (S235)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 75

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 76

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> AAK1 (S235)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 76

Ala Pro Glu Met Val Asn Leu Tyr Ser Gly Lys

1 5 10

<210> 77

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MNK2 (S74)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 77

Ala Thr Asp Ser Phe Ser Gly Arg

1 5

<210> 78

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TYK2 (1054)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 78

Ala Val Pro Glu Gly His Glu Tyr Tyr Arg

1 5 10

<210> 79

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11B (Y594)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 79

Ala Tyr Thr Pro Val Val Val Thr Leu Trp Tyr Arg

1 5 10

<210> 80

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11B (Y594/T595)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 80

Ala Tyr Thr Pro Val Val Val Thr Leu Trp Tyr Arg

1 5 10

<210> 81

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11B (T595)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 81

Ala Tyr Thr Pro Val Val Val Thr Leu Trp Tyr Arg

1 5 10

<210> 82

<211> 17

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MSK1 (S212)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 82

Ala Tyr Ser Phe Cys Gly Thr Ile Glu Tyr Met Ala Pro Asp Ile Val

1 5 10 15

Arg

<210> 83

<211> 17

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MSK1 (S212)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 83

Ala Tyr Ser Phe Cys Gly Thr Ile Glu Tyr Met Ala Pro Asp Ile Val

1 5 10 15

Arg

<210> 84

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGR (412)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 84

Asp Asp Glu Tyr Asn Pro Cys Gln Gly Ser Lys

1 5 10

<210> 85

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> SRMS (Y849)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 85

Asp Asp Ile Tyr Ser Pro Ser Ser Ser Ser Lys

1 5 10

<210> 86

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PGFRA (Y849)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 86

Asp Ile Met His Asp Ser Asn Tyr Val Ser Lys

1 5 10

<210> 87

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PGFRA (Y849)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 87

Asp Ile Met His Asp Ser Asn Tyr Val Ser Lys

1 5 10

<210> 88

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR1 (Y653)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 88

Asp Ile His His Ile Asp Tyr Tyr Lys

1 5

<210> 89

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR1 (Y654)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 89

Asp Ile His His Ile Asp Tyr Tyr Lys

1 5

<210> 90

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CSF1R (Y809)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 90

Asp Ile Met Asn Asp Ser Asn Tyr Ile Val Lys

1 5 10

<210> 91

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CSF1R (Y809)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 91

Asp Ile Met Asn Asp Ser Asn Tyr Ile Val Lys

1 5 10

<210> 92

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FLT3 (Y842)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 92

Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg

1 5 10

<210> 93

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FLT3 (Y842)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 93

Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg

1 5 10

<210> 94

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR2 (Y656)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 94

Asp Ile Asn Asn Ile Asp Tyr Tyr Lys

1 5

<210> 95

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR2 (Y656/Y657)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 95

Asp Ile Asn Asn Ile Asp Tyr Tyr Lys

1 5

<210> 96

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR2 (Y657)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 96

Asp Ile Asn Asn Ile Asp Tyr Tyr Lys

1 5

<210> 97

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkA (Y676)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 97

Asp Ile Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 98

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkA (Y680)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 98

Asp Ile Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 99

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TrkA (Y681)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 99

Asp Ile Tyr Ser Thr Asp Tyr Tyr Arg

1 5

<210> 100

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PDGFRβ (Y857)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 100

Asp Ser Asn Tyr Ile Ser Lys

1 5

<210> 101

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR3 (Y647)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 101

Asp Val His Asn Leu Asp Tyr Tyr Lys

1 5

<210> 102

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR3 (Y647/Y648)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 102

Asp Val His Asn Leu Asp Tyr Tyr Lys

1 5

<210> 103

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RET (Y900)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 103

Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys

1 5 10

<210> 104

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RET (Y900/Y905)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 104

Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys

1 5 10

<210> 105

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RET (Y905)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 105

Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys

1 5 10

<210> 106

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRR (Y1145)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 106

Asp Val Tyr Glu Thr Asp Tyr Tyr Arg

1 5

<210> 107

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRR (Y1145/Y1146)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 107

Asp Val Tyr Glu Thr Asp Tyr Tyr Arg

1 5

<210> 108

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRR (Y1146)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 108

Asp Val Tyr Glu Thr Asp Tyr Tyr Arg

1 5

<210> 109

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PTK6 (Y342)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 109

Glu Asp Val Tyr Leu Ser His Asp His Asn Ile Pro Tyr Lys

1 5 10

<210> 110

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PTK6 (Y342/Y351)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 110

Glu Asp Val Tyr Leu Ser His Asp His Asn Ile Pro Tyr Lys

1 5 10

<210> 111

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PTK6 (Y351)

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 111

Glu Asp Val Tyr Leu Ser His Asp His Asn Ile Pro Tyr Lys

1 5 10

<210> 112

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FES (Y713)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 112

Glu Glu Ala Asp Gly Val Tyr Ala Ala Ser Gly Gly Leu Arg

1 5 10

<210> 113

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ROR1 (Y645)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 113

Glu Ile Tyr Ser Ala Asp Tyr Tyr Arg

1 5

<210> 114

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KPCD (S503)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 114

Glu Asn Ile Phe Gly Glu Ser Arg

1 5

<210> 115

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TESK1 (S220)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 115

Glu Pro Leu Ala Val Val Gly Ser Pro Tyr Trp Met Ala Pro Glu Val

1 5 10 15

Leu Arg

<210> 116

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TESK1 (S220)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 12

<223> phosphorylation

<400> 116

Glu Pro Leu Ala Val Val Gly Ser Pro Tyr Trp Met Ala Pro Glu Val

1 5 10 15

Leu Arg

<210> 117

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ROR2 (Y646)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 117

Glu Val Tyr Ala Ala Asp Tyr Tyr Lys

1 5

<210> 118

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11A (Y582)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 118

Ala Tyr Thr Pro Val Val Val Thr Gln Trp Tyr Arg

1 5 10

<210> 119

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK11A (Y582/T583)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 119

Ala Tyr Thr Pro Val Val Val Thr Gln Trp Tyr Arg

1 5 10

<210> 120

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MET (Y1234)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 120

Glu Tyr Tyr Ser Val His Asn Lys

1 5

<210> 121

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MET (Y1234/Y1235)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 121

Glu Tyr Tyr Ser Val His Asn Lys

1 5

<210> 122

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MET (Y1235)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 122

Glu Tyr Tyr Ser Val His Asn Lys

1 5

<210> 123

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RON (Y1238)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 123

Glu Tyr Tyr Ser Val Gln Gln His Arg

1 5

<210> 124

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RON (Y1238/Y1239)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 124

Glu Tyr Tyr Ser Val Gln Gln His Arg

1 5

<210> 125

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RON (Y1239)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 125

Glu Tyr Tyr Ser Val Gln Gln His Arg

1 5

<210> 126

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK1 (Y1034)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 126

Glu Tyr Tyr Thr Val Lys

1 5

<210> 127

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK1 (Y1035)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 127

Glu Tyr Tyr Thr Val Lys

1 5

<210> 128

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK1 (Y1034/Y1035)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 128

Glu Tyr Tyr Thr Val Lys

1 5

<210> 129

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JAK1 (Y1035)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 129

Glu Tyr Tyr Thr Val Lys

1 5

<210> 130

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRAK4 (T345)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 130

Phe Ala Gln Thr Val Met Thr Ser Arg

1 5

<210> 131

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRAK4 (T345)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 131

Phe Ala Gln Thr Val Met Thr Ser Arg

1 5

<210> 132

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRAK4 (S346)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 132

Phe Ala Gln Thr Val Met Thr Ser Arg

1 5

<210> 133

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRAK4 (S346)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 133

Phe Ala Gln Thr Val Met Thr Ser Arg

1 5

<210> 134

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK6 (T202)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 134

Phe Phe Ser Ser Glu Thr Thr Ala Ala His Ser Leu Val Gly Thr Pro

1 5 10 15

Tyr Tyr Met Ser Pro Glu Arg

20

<210> 135

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK6 (T202)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 19

<223> phosphorylation

<400> 135

Phe Phe Ser Ser Glu Thr Thr Ala Ala His Ser Leu Val Gly Thr Pro

1 5 10 15

Tyr Tyr Met Ser Pro Glu Arg

20

<210> 136

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK6 (S206)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 136

Phe Phe Ser Ser Glu Thr Thr Ala Ala His Ser Leu Val Gly Thr Pro

1 5 10 15

Tyr Tyr Met Ser Pro Glu Arg

20

<210> 137

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK6 (S206)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 19

<223> phosphorylation

<400> 137

Phe Phe Ser Ser Glu Thr Thr Ala Ala His Ser Leu Val Gly Thr Pro

1 5 10 15

Tyr Tyr Met Ser Pro Glu Arg

20

<210> 138

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ITK (Y512)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 138

Phe Val Leu Asp Asp Gln Tyr Thr Ser Ser Thr Gly Thr Lys

1 5 10

<210> 139

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IKKE (S172)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 139

Phe Val Ser Val Tyr Gly Thr Glu Glu Tyr Leu His Pro Asp Met Tyr

1 5 10 15

Glu Arg

<210> 140

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IKKE (S172)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 15

<223> phosphorylation

<400> 140

Phe Val Ser Val Tyr Gly Thr Glu Glu Tyr Leu His Pro Asp Met Tyr

1 5 10 15

Glu Arg

<210> 141

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC1D (T180)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 141

Gly Asp Val Met Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro

1 5 10 15

Glu Val Leu Ala Gln Lys

20

<210> 142

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KCC1D (T180)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 142

Gly Asp Val Met Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro

1 5 10 15

Glu Val Leu Ala Gln Lys

20

<210> 143

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK06 (S189)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 143

Gly His Leu Ser Glu Gly Leu Val Thr Lys

1 5 10

<210> 144

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K7 (S192)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 144

Gly Ser Ala Ala Trp Met Ala Pro Glu Val Phe Glu Gly Ser Asn Tyr

1 5 10 15

Ser Glu Lys

<210> 145

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TIE2 (Y992)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 145

Gly Gln Glu Val Tyr Val Lys

1 5

<210> 146

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K7 (S192)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 146

Gly Ser Ala Ala Trp Met Ala Pro Glu Val Phe Glu Gly Ser Asn Tyr

1 5 10 15

Ser Glu Lys

<210> 147

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RK (S21)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 147

Gly Ser Phe Asp Gly Ser Ser Ser Gln Pro Ser Arg

1 5 10

<210> 148

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ULK3 (S176)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 12

<223> phosphorylation

<400> 148

Gly Ser Pro Leu Tyr Met Ala Pro Glu Met Val Cys Gln Arg

1 5 10

<210> 149

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ULK3 (S176)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 12

<223> phosphorylation

<400> 149

Gly Ser Pro Leu Tyr Met Ala Pro Glu Met Val Cys Gln Arg

1 5 10

<210> 150

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K8 (T290)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 150

Gly Thr Glu Ile Tyr Met Ser Pro Glu Val Ile Leu Cys Arg

1 5 10

<210> 151

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3K8 (T290)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 151

Gly Thr Glu Ile Tyr Met Ser Pro Glu Val Ile Leu Cys Arg

1 5 10

<210> 152

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> IRAK1 (T387)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 152

Gly Thr Leu Ala Tyr Leu Pro Glu Glu Tyr Ile Lys

1 5 10

<210> 153

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR4 (Y642)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 153

Gly Val His His Ile Asp Tyr Tyr Lys

1 5

<210> 154

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR4 (Y642/Y643)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 154

Gly Val His His Ile Asp Tyr Tyr Lys

1 5

<210> 155

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FGFR4 (Y643)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 155

Gly Val His His Ile Asp Tyr Tyr Lys

1 5

<210> 156

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK04 (S186)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 156

Gly Tyr Leu Ser Glu Gly Leu Val Thr Lys

1 5 10

<210> 157

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (T180)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 157

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 158

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 158

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 159

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 159

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 160

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (T180)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 160

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 161

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (Y182)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 161

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 162

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38δ (Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 162

His Ala Asp Ala Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 163

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NLK (T298)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 163

His Met Thr Gln Glu Val Val Thr Gln Tyr Tyr Arg

1 5 10

<210> 164

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NLK (T298)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 164

His Met Thr Gln Glu Val Val Thr Gln Tyr Tyr Arg

1 5 10

<210> 165

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (T180)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 165

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 166

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 166

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 167

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 167

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 168

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (T180)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 168

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 169

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (Y182)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 169

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 170

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MK14 (Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 170

His Thr Asp Asp Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 171

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RIPK1 (S161)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 171

Ile Ala Asp Leu Gly Leu Ala Ser Phe Lys

1 5 10

<210> 172

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ERK1 (T198)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 172

Ile Ala Asp Pro Glu His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 173

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ERK1 (T202)

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 173

Ile Ala Asp Pro Glu His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 174

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> ERK1 (Y204)

<220>

<221> post-translational modification of residue

<222> 15

<223> phosphorylation

<400> 174

Ile Ala Asp Pro Glu His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 175

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MLTK (S155)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 175

Ile Cys Asp Phe Gly Ala Ser Arg

1 5

<210> 176

<211> 25

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MAPK5 (T182)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 176

Ile Asp Gln Gly Asp Leu Met Thr Pro Gln Phe Thr Pro Tyr Tyr Val

1 5 10 15

Ala Pro Gln Val Leu Glu Ala Gln Arg

20 25

<210> 177

<211> 25

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MAPK5 (T182)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 177

Ile Asp Gln Gly Asp Leu Met Thr Pro Gln Phe Thr Pro Tyr Tyr Val

1 5 10 15

Ala Pro Gln Val Leu Glu Ala Gln Arg

20 25

<210> 178

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> BLK (Y389)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 178

Ile Ile Asp Ser Glu Tyr Thr Ala Gln Glu Gly Ala Lys

1 5 10

<210> 179

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> UFO (Y703)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 179

Ile Tyr Asn Gly Asp Tyr Tyr Arg

1 5

<210> 180

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MERTK (Y749) TYRO3 (Y681)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 180

Ile Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 181

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MERTK (Y753) TYRO3 (Y685)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 181

Ile Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 182

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MERTK (Y754) TYRO3 (Y686)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 182

Ile Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 183

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TESK2 (S219)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 183

Leu Ala Val Val Gly Ser Pro Phe Trp Met Ala Pro Glu Val Leu Arg

1 5 10 15

<210> 184

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TESK2 (S219)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 184

Leu Ala Val Val Gly Ser Pro Phe Trp Met Ala Pro Glu Val Leu Arg

1 5 10 15

<210> 185

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MKK4 (S2570

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 185

Leu Cys Asp Phe Gly Ile Ser Gly Gln Leu Val Asp Ser Ile Ala Lys

1 5 10 15

<210> 186

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MRCKG (S216)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 186

Leu Ala Asp Phe Gly Ser Cys Leu Arg

1 5

<210> 187

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MARK1 (T208)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 187

Ile Ala Asp Phe Gly Phe Ser Asn Glu Phe Thr Val Gly Asn Lys

1 5 10 15

<210> 188

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Dyrk3 (Y369)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 188

Leu Tyr Thr Tyr Ile Gln Ser Arg

1 5

<210> 189

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> RIPK2 (S176)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 189

Met Met Ser Leu Ser Gln Ser Arg

1 5

<210> 190

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> RIPK2 (S176)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 190

Met Met Ser Leu Ser Gln Ser Arg

1 5

<210> 191

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> M3KL4 (S303)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 191

Met Ser Thr Ala Gly Thr Tyr Ala Trp Met Ala Pro Glu Val Ile Lys

1 5 10 15

<210> 192

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> M3KL4 (S303)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 192

Met Ser Thr Ala Gly Thr Tyr Ala Trp Met Ala Pro Glu Val Ile Lys

1 5 10 15

<210> 193

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KIT (S821)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 193

Asn Asp Ser Asn Tyr Val Val Lys

1 5

<210> 194

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KIT (S821/Y823)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 194

Asn Asp Ser Asn Tyr Val Val Lys

1 5

<210> 195

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> KIT (Y823)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 195

Asn Asp Ser Asn Tyr Val Val Lys

1 5

<210> 196

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MUSK (Y755)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 196

Asn Ile Tyr Ser Ala Asp Tyr Tyr Lys

1 5

<210> 197

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR1 (Y792)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 197

Asn Leu Tyr Ala Gly Asp Tyr Tyr Arg

1 5

<210> 198

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR1 (Y796)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 198

Asn Leu Tyr Ala Gly Asp Tyr Tyr Arg

1 5

<210> 199

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR1 (Y797)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 199

Asn Leu Tyr Ala Gly Asp Tyr Tyr Arg

1 5

<210> 200

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR2 (Y736)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 200

Asn Leu Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 201

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR2 (Y740)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 201

Asn Leu Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 202

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> DDR2 (Y741)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 202

Asn Leu Tyr Ser Gly Asp Tyr Tyr Arg

1 5

<210> 203

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> BMPR2 (T379)

<220>

<221> post-translational modification of residue

<222> 14

<223> phosphorylation

<400> 203

Pro Gly Glu Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg

1 5 10 15

<210> 204

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (T180)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 204

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 205

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 205

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 206

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (T180/Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 206

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 207

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (T180)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 207

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 208

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (Y182)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 208

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 209

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38B (Y182)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 209

Gln Ala Asp Glu Glu Met Thr Gly Tyr Val Ala Thr Arg

1 5 10

<210> 210

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (T183)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 210

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 211

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (T183/Y185)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 211

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 212

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (T183/Y185)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 212

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 213

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (T183)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 213

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 214

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (Y185)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 214

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 215

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> P38G (Y185)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 215

Gln Ala Asp Ser Glu Met Thr Gly Tyr Val Val Thr Arg

1 5 10

<210> 216

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MPSK1 (T185)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 216

Gln Ala Leu Thr Leu Gln Asp Trp Ala Ala Gln Arg

1 5 10

<210> 217

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MPSK1 (S197)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 217

Cys Thr Ile Ser Tyr Arg

1 5

<210> 218

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MPSK1 (S197/Y198)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 218

Cys Thr Ile Ser Tyr Arg

1 5

<210> 219

<211> 6

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MPSK1 (Y198)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 219

Cys Thr Ile Ser Tyr Arg

1 5

<210> 220

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Fer (Y714)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 220

Gln Glu Asp Gly Gly Val Tyr Ser Ser Ser Gly Leu Lys

1 5 10

<210> 221

<211> 8

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CaMKIIβ (T287)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 221

Gln Glu Thr Val Glu Cys Leu Lys

1 5

<210> 222

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK12 (S1053)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 222

Gln Ser Gly Val Val Val Glu Glu Pro Pro Pro Ser Lys

1 5 10

<210> 223

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK12 (S1083)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 223

Asn Ser Ser Pro Ala Pro Pro Gln Pro Ala Pro Gly Lys

1 5 10

<210> 224

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PAK4 (S475)

<400> 224

Ser Leu Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Leu Ile Ser Arg

1 5 10 15

<210> 225

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PAK4 (S475)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 225

Ser Leu Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Leu Ile Ser Arg

1 5 10 15

<210> 226

<211> 26

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GCN2 (T899)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 226

Ser Asp Pro Ser Gly His Leu Thr Gly Met Val Gly Thr Ala Leu Tyr

1 5 10 15

Val Ser Pro Glu Val Gln Gly Ser Thr Lys

20 25

<210> 227

<211> 26

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GCN2 (T899)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 227

Ser Asp Pro Ser Gly His Leu Thr Gly Met Val Gly Thr Ala Leu Tyr

1 5 10 15

Val Ser Pro Glu Val Gln Gly Ser Thr Lys

20 25

<210> 228

<211> 26

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GCN2 (T904)

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 228

Ser Asp Pro Ser Gly His Leu Thr Gly Met Val Gly Thr Ala Leu Tyr

1 5 10 15

Val Ser Pro Glu Val Gln Gly Ser Thr Lys

20 25

<210> 229

<211> 26

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GCN2 (T904)

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 229

Ser Asp Pro Ser Gly His Leu Thr Gly Met Val Gly Thr Ala Leu Tyr

1 5 10 15

Val Ser Pro Glu Val Gln Gly Ser Thr Lys

20 25

<210> 230

<211> 22

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Her4 (Y1056)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 230

Ser Glu Ile Gly His Ser Pro Pro Pro Ala Tyr Thr Pro Met Ser Gly

1 5 10 15

Asn Gln Phe Val Tyr Arg

20

<210> 231

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK7 (S164)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 231

Ser Phe Gly Ser Pro Asn Arg

1 5

<210> 232

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK7 (T170)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 232

Ala Tyr Thr His Gln Val Val Thr Arg

1 5

<210> 233

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MASTL (S293)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 233

Cys Leu Thr Ser Asn Leu Leu Gln Ser Arg

1 5 10

<210> 234

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MASTL (S552)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 234

Asp Tyr Leu Ser Ser Ser Phe Leu Cys Ser Asp Asp Asp Arg

1 5 10

<210> 235

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MASTL (S552/S556)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 235

Asp Tyr Leu Ser Ser Ser Phe Leu Cys Ser Asp Asp Asp Arg

1 5 10

<210> 236

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MASTL (S631)

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 236

Gly Val Glu Asn Pro Ala Val Gln Glu Ser Asn Gln Lys

1 5 10

<210> 237

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MASTL (S657)

<400> 237

Ser Phe Asn Ser His Ile Asn Ala Ser Asn Asn Ser Glu Pro Ser Arg

1 5 10 15

<210> 238

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MASTL (S657/S668)

<220>

<221> post-translational modification of residue

<222> 12

<223> phosphorylation

<400> 238

Ser Phe Asn Ser His Ile Asn Ala Ser Asn Asn Ser Glu Pro Ser Arg

1 5 10 15

<210> 239

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MASTL (S668)

<220>

<221> post-translational modification of residue

<222> 12

<223> phosphorylation

<400> 239

Ser Phe Asn Ser His Ile Asn Ala Ser Asn Asn Ser Glu Pro Ser Arg

1 5 10 15

<210> 240

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MASTL (T741)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 240

Ile Leu Gly Thr Pro Asp Tyr Leu Ala Pro Glu Leu Leu Leu Gly Arg

1 5 10 15

<210> 241

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> SIK (T182)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 241

Ser Gly Glu Pro Leu Ser Thr Trp Cys Gly Ser Pro Pro Tyr Ala Ala

1 5 10 15

Pro Glu Val Phe Glu Gly Lys

20

<210> 242

<211> 21

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PRKD2 (S710)

<400> 242

Ser Val Val Gly Thr Pro Ala Tyr Leu Ala Pro Glu Val Leu Leu Asn

1 5 10 15

Gln Gly Tyr Asn Arg

20

<210> 243

<211> 21

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PRKD2 (Y717)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 243

Ser Val Val Gly Thr Pro Ala Tyr Leu Ala Pro Glu Val Leu Leu Asn

1 5 10 15

Gln Gly Tyr Asn Arg

20

<210> 244

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PLK2 (T239)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 244

Thr Ile Cys Gly Thr Pro Asn Tyr Leu Ser Pro Glu Val Leu Asn Lys

1 5 10 15

<210> 245

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Chk2/Rad53 (S379)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 245

Ile Leu Gly Glu Thr Ser Leu Met Arg

1 5

<210> 246

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Chk2/Rad53 (S379)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 246

Ile Leu Gly Glu Thr Ser Leu Met Arg

1 5

<210> 247

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> CaMK4 (T200)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 247

Thr Val Cys Gly Thr Pro Gly Tyr Cys Ala Pro Glu Ile Leu Arg

1 5 10 15

<210> 248

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MEK5 (T315)

<400> 248

Thr Tyr Val Gly Thr Asn Ala Tyr Met Ala Pro Glu Arg

1 5 10

<210> 249

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MEK5 (T315)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 249

Thr Tyr Val Gly Thr Asn Ala Tyr Met Ala Pro Glu Arg

1 5 10

<210> 250

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK2 (T183)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 250

Thr Ala Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 251

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK2 (T183/Y185)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 251

Thr Ala Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 252

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK2 (T183/Y185)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 252

Thr Ala Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 253

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK2 (Y185)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 253

Thr Ala Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 254

<211> 15

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> JNK2 (Y185)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 254

Thr Ala Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg

1 5 10 15

<210> 255

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK2 (T170)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 255

Ile Leu Asn His Asp Thr Ser Phe Ala Lys

1 5 10

<210> 256

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK2 (T170/S171)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 256

Ile Leu Asn His Asp Thr Ser Phe Ala Lys

1 5 10

<210> 257

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK2 (S171)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 257

Ile Leu Asn His Asp Thr Ser Phe Ala Lys

1 5 10

<210> 258

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> NEK2 (T175)

<400> 258

Thr Phe Val Gly Thr Pro Tyr Tyr Met Ser Pro Glu Gln Met Asn Arg

1 5 10 15

<210> 259

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> NEK2 (T179)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 259

Thr Phe Val Gly Thr Pro Tyr Tyr Met Ser Pro Glu Gln Met Asn Arg

1 5 10 15

<210> 260

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PLK1 (T210)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 260

Thr Leu Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Val Leu Ser Lys

1 5 10 15

<210> 261

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> PLK1 (T210/T214)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 261

Thr Leu Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Val Leu Ser Lys

1 5 10 15

<210> 262

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PLK1 (T214)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 262

Thr Leu Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Val Leu Ser Lys

1 5 10 15

<210> 263

<211> 20

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKCθ (T538)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 263

Thr Asn Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Leu

1 5 10 15

Leu Gly Gln Lys

20

<210> 264

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MLKL (S358)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 264

Thr Gln Thr Ser Met Ser Leu Gly Thr Thr Arg

1 5 10

<210> 265

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MLKL (S358)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 265

Thr Gln Thr Ser Met Ser Leu Gly Thr Thr Arg

1 5 10

<210> 266

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MLKL (S360)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 266

Thr Gln Thr Ser Met Ser Leu Gly Thr Thr Arg

1 5 10

<210> 267

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> MLKL (S360)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 267

Thr Gln Thr Ser Met Ser Leu Gly Thr Thr Arg

1 5 10

<210> 268

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKN2 (T816)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 268

Thr Ser Thr Phe Cys Gly Thr Pro Glu Phe Leu Ala Pro Glu Val Leu

1 5 10 15

Thr Glu Thr Ser Tyr Thr Arg

20

<210> 269

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKN2 (T820)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 269

Thr Ser Thr Phe Cys Gly Thr Pro Glu Phe Leu Ala Pro Glu Val Leu

1 5 10 15

Thr Glu Thr Ser Tyr Thr Arg

20

<210> 270

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKN3 (T718)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 270

Thr Ser Thr Phe Cys Gly Thr Pro Glu Phe Leu Ala Pro Glu Val Leu

1 5 10 15

Thr Gln Glu Ala Tyr Thr Arg

20

<210> 271

<211> 23

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PKN3 (T722)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 271

Thr Ser Thr Phe Cys Gly Thr Pro Glu Phe Leu Ala Pro Glu Val Leu

1 5 10 15

Thr Gln Glu Ala Tyr Thr Arg

20

<210> 272

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> MLK3 (T277)

<400> 272

Thr Thr Gln Met Ser Ala Ala Gly Thr Tyr Ala Trp Met Ala Pro Glu

1 5 10 15

Val Ile Lys

<210> 273

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> HIPK3 (Y359)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 273

Thr Val Cys Ser Thr Tyr Leu Gln Ser Arg

1 5 10

<210> 274

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Erk2 (T185)

<220>

<221> post-translational modification of residue

<222> 13

<223> phosphorylation

<400> 274

Val Ala Asp Pro Asp His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 275

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Erk2 (Y187)

<220>

<221> post-translational modification of residue

<222> 15

<223> phosphorylation

<400> 275

Val Ala Asp Pro Asp His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 276

<211> 19

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Erk2 (T190)

<220>

<221> post-translational modification of residue

<222> 18

<223> phosphorylation

<400> 276

Val Ala Asp Pro Asp His Asp His Thr Gly Phe Leu Thr Glu Tyr Val

1 5 10 15

Ala Thr Arg

<210> 277

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FRK (Y387)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 277

Val Asp Asn Glu Asp Ile Tyr Glu Ser Arg

1 5 10

<210> 278

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA7 (Y791)

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 278

Val Ile Glu Asp Asp Pro Glu Ala Val Tyr Thr Thr Thr Gly Gly Lys

1 5 10 15

<210> 279

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA6 (Y830)

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 279

Val Leu Glu Asp Asp Pro Glu Ala Ala Tyr Thr Thr Thr Gly Gly Lys

1 5 10 15

<210> 280

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GAK (S456)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 280

His Pro Gly His Tyr Ala Val Tyr Asn Leu Ser Pro Arg

1 5 10

<210> 281

<211> 21

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GAK (S829)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 281

Asp Glu Ser Glu Val Ser Asp Glu Gly Gly Ser Pro Ile Ser Ser Glu

1 5 10 15

Gly Gln Glu Pro Arg

20

<210> 282

<211> 21

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GAK (S834)

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 282

Asp Glu Ser Glu Val Ser Asp Glu Gly Gly Ser Pro Ile Ser Ser Glu

1 5 10 15

Gly Gln Glu Pro Arg

20

<210> 283

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GAK (S1176)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 283

Val Ser Glu Asn Asp Phe Glu Asp Leu Leu Ser Asn Gln Gly Phe Ser

1 5 10 15

Ser Arg

<210> 284

<211> 18

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> GAK (S1176&S1185)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 11

<223> phosphorylation

<400> 284

Val Ser Glu Asn Asp Phe Glu Asp Leu Leu Ser Asn Gln Gly Phe Ser

1 5 10 15

Ser Arg

<210> 285

<211> 21

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CLK2 (T344)

<220>

<221> post-translational modification of residue

<222> 20

<223> phosphorylation

<400> 285

Val Val Asp Phe Gly Ser Ala Thr Phe Asp His Glu His His Ser Thr

1 5 10 15

Ile Val Ser Thr Arg

20

<210> 286

<211> 12

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK1 (T161)

<220>

<221> post-translational modification of residue

<222> 3

<223> phosphorylation

<400> 286

Val Tyr Thr His Glu Val Val Thr Leu Trp Tyr Arg

1 5 10

<210> 287

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> CDK1 (S178)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 287

Ser Pro Glu Val Leu Leu Gly Ser Ala Arg

1 5 10

<210> 288

<211> 16

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA2 (T771/Y772)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 10

<223> phosphorylation

<400> 288

Val Leu Glu Asp Asp Pro Glu Ala Thr Tyr Thr Thr Ser Gly Gly Lys

1 5 10 15

<210> 289

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA2 (S790)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 289

Trp Thr Ala Pro Glu Ala Ile Ser Tyr Arg

1 5 10

<210> 290

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA2 (S790/Y791)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 290

Trp Thr Ala Pro Glu Ala Ile Ser Tyr Arg

1 5 10

<210> 291

<211> 10

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> EphA2 (Y791)

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 291

Trp Thr Ala Pro Glu Ala Ile Ser Tyr Arg

1 5 10

<210> 292

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Syk (Y525)

<220>

<221> post-translational modification of residue

<222> 5

<223> phosphorylation

<400> 292

Ala Asp Glu Asn Tyr Tyr Lys

1 5

<210> 293

<211> 7

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Syk (Y526)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<400> 293

Ala Asp Glu Asn Tyr Tyr Lys

1 5

<210> 294

<211> 11

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> Syk (Y546)

<220>

<221> post-translational modification of residue

<222> 6

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 9

<223> phosphorylation

<400> 294

Trp Tyr Ala Pro Glu Cys Ile Asn Tyr Tyr Lys

1 5 10

<210> 295

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TTN (S9203)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<400> 295

Val Ala Gly Ser Gln Pro Ile Thr Val Ala Trp Tyr Lys

1 5 10

<210> 296

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TTN (S9203/T9207)

<220>

<221> post-translational modification of residue

<222> 4

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 296

Val Ala Gly Ser Gln Pro Ile Thr Val Ala Trp Tyr Lys

1 5 10

<210> 297

<211> 13

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TTN (T9207)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 297

Val Ala Gly Ser Gln Pro Ile Thr Val Ala Trp Tyr Lys

1 5 10

<210> 298

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> FAK (Y570)

<400> 298

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 299

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<221> post-translational modification of residue

<222> 1

<223> phosphorylation

<220>

<223> FAK (Y570)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<400> 299

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 300

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FAK (Y576)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 300

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 301

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FAK (Y576)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 301

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 302

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FAK (Y577)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 302

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 303

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> FAK (Y577)

<220>

<221> post-translational modification of residue

<222> 2

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 303

Tyr Met Glu Asp Ser Thr Tyr Tyr Lys

1 5

<210> 304

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PYK2/FAK2 (Y579)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 304

Tyr Ile Glu Asp Glu Asp Tyr Tyr Lys

1 5

<210> 305

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PYK2/FAK2 (Y579/Y580)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 305

Tyr Ile Glu Asp Glu Asp Tyr Tyr Lys

1 5

<210> 306

<211> 9

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> PYK2/FAK2 (Y580)

<220>

<221> post-translational modification of residue

<222> 8

<223> phosphorylation

<400> 306

Tyr Ile Glu Asp Glu Asp Tyr Tyr Lys

1 5

<210> 307

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> BTK (Y551)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 307

Tyr Val Leu Asp Asp Glu Tyr Thr Ser Ser Val Gly Ser Lys

1 5 10

<210> 308

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TXK (Y420)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 308

Tyr Val Leu Asp Asp Glu Tyr Val Ser Ser Phe Gly Ala Lys

1 5 10

<210> 309

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> TEC (Y519)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 309

Tyr Val Leu Asp Asp Gln Tyr Thr Ser Ser Ser Gly Ala Lys

1 5 10

<210> 310

<211> 14

<212> PRT

<213> Intelligent (Homo sapiens)

<220>

<223> BMX (Y566)

<220>

<221> post-translational modification of residue

<222> 7

<223> phosphorylation

<400> 310

Tyr Val Leu Asp Asp Gln Tyr Val Ser Ser Val Gly Thr Lys

1 5 10