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Title: An integrative analysis of tumor proteomic and phosphoproteomic profiles to examine the relationships between kinase activity and phosphorylation

Abstract

Phosphorylation of proteins is a key way cells regulate function, both at the individual protein level and at the level of signaling pathways. Kinases are responsible for phosphorylation of substrates, generally on serine, threonine, or tyrosine residues. Though particular sequence patterns can be identified that dictate whether a residue will be phosphorylated by a specific kinase, these patterns are not highly predictive of phosphorylation. The availability of large scale proteomic and phosphoproteomic datasets generated using mass-spectrometry-based approaches provides an opportunity to study the important relationship between kinase activity, substrate specificity, and phosphorylation. In this study, we analyze relationships between protein abundance and phosphopeptide abundance across more than 150 tumor samples and show that phosphorylation at specific phosphosites is not well correlated with overall kinase abundance. However, individual kinases show a clear and statistically significant difference in correlation between known phosphosite targets for that kinase and randomly selected phosphosites. We further investigate relationships between phosphorylation of known activating or inhibitory sites on kinases and phosphorylation of their target phosphosites. Combined with motif-based analysis, this approach can predict novel kinase targets and show which subsets of a kinase’s target repertoire are specifically active in one condition versus another.

Authors:
 [1];  [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]
  1. BATTELLE (PACIFIC NW LAB)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1572488
Report Number(s):
PNNL-SA-145629
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Molecular and Cellular Proteomics
Additional Journal Information:
Journal Volume: 18; Journal Issue: 8 suppl 1
Country of Publication:
United States
Language:
English
Subject:
post-translational modification, kinase, phosphorylation, cancer, systems biology

Citation Formats

Arshad, Osama A., Danna, Vincent G., Petyuk, Vladislav A., Piehowski, Paul D., Liu, Tao, Rodland, Karin D., and McDermott, Jason E. An integrative analysis of tumor proteomic and phosphoproteomic profiles to examine the relationships between kinase activity and phosphorylation. United States: N. p., 2019. Web. doi:10.1074/mcp.RA119.001540.
Arshad, Osama A., Danna, Vincent G., Petyuk, Vladislav A., Piehowski, Paul D., Liu, Tao, Rodland, Karin D., & McDermott, Jason E. An integrative analysis of tumor proteomic and phosphoproteomic profiles to examine the relationships between kinase activity and phosphorylation. United States. doi:10.1074/mcp.RA119.001540.
Arshad, Osama A., Danna, Vincent G., Petyuk, Vladislav A., Piehowski, Paul D., Liu, Tao, Rodland, Karin D., and McDermott, Jason E. Fri . "An integrative analysis of tumor proteomic and phosphoproteomic profiles to examine the relationships between kinase activity and phosphorylation". United States. doi:10.1074/mcp.RA119.001540.
@article{osti_1572488,
title = {An integrative analysis of tumor proteomic and phosphoproteomic profiles to examine the relationships between kinase activity and phosphorylation},
author = {Arshad, Osama A. and Danna, Vincent G. and Petyuk, Vladislav A. and Piehowski, Paul D. and Liu, Tao and Rodland, Karin D. and McDermott, Jason E.},
abstractNote = {Phosphorylation of proteins is a key way cells regulate function, both at the individual protein level and at the level of signaling pathways. Kinases are responsible for phosphorylation of substrates, generally on serine, threonine, or tyrosine residues. Though particular sequence patterns can be identified that dictate whether a residue will be phosphorylated by a specific kinase, these patterns are not highly predictive of phosphorylation. The availability of large scale proteomic and phosphoproteomic datasets generated using mass-spectrometry-based approaches provides an opportunity to study the important relationship between kinase activity, substrate specificity, and phosphorylation. In this study, we analyze relationships between protein abundance and phosphopeptide abundance across more than 150 tumor samples and show that phosphorylation at specific phosphosites is not well correlated with overall kinase abundance. However, individual kinases show a clear and statistically significant difference in correlation between known phosphosite targets for that kinase and randomly selected phosphosites. We further investigate relationships between phosphorylation of known activating or inhibitory sites on kinases and phosphorylation of their target phosphosites. Combined with motif-based analysis, this approach can predict novel kinase targets and show which subsets of a kinase’s target repertoire are specifically active in one condition versus another.},
doi = {10.1074/mcp.RA119.001540},
journal = {Molecular and Cellular Proteomics},
number = 8 suppl 1,
volume = 18,
place = {United States},
year = {2019},
month = {8}
}

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