Construction of human activity-based phosphorylation networks

Robert H. Newman, Jianfei Hu, Hee Sool Rho, Zhi Xie, Crystal Woodard, John Neiswinger, Christopher Cooper, Matthew Shirley, Hillary M. Clark, Shaohui Hu, Woochang Hwang, Jun Seop Jeong, George Wu, Jimmy Lin, Xinxin Gao, Qiang Ni, Renu Goel, Shuli Xia, Hongkai Ji, Kevin N. DalbyMorris J. Birnbaum, Philip A. Cole, Stefan Knapp, Alexey G. Ryazanov, Donald J. Zack, Seth Blackshaw, Tony Pawson, Anne Claude Gingras, Stephen Desiderio, Akhilesh Pandey, Benjamin E. Turk, Jin Zhang, Heng Zhu, Jiang Qian

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

The landscape of human phosphorylation networks has not been systematically explored, representing vast, unchartered territories within cellular signaling networks. Although a large number of in vivo phosphorylated residues have been identified by mass spectrometry (MS)-based approaches, assigning the upstream kinases to these residues requires biochemical analysis of kinase-substrate relationships (KSRs). Here, we developed a new strategy, called CEASAR, based on functional protein microarrays and bioinformatics to experimentally identify substrates for 289 unique kinases, resulting in 3656 high-quality KSRs. We then generated consensus phosphorylation motifs for each of the kinases and integrated this information, along with information about in vivo phosphorylation sites determined by MS, to construct a high-resolution map of phosphorylation networks that connects 230 kinases to 2591 in vivo phosphorylation sites in 652 substrates. The value of this data set is demonstrated through the discovery of a new role for PKA downstream of Btk (Bruton's tyrosine kinase) during B-cell receptor signaling. Overall, these studies provide global insights into kinase-mediated signaling pathways and promise to advance our understanding of cellular signaling processes in humans.

Original languageEnglish (US)
Article number655
JournalMolecular Systems Biology
Volume9
DOIs
StatePublished - Jan 1 2013

Keywords

  • phosphorylation
  • signaling networks
  • systems biology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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    Newman, R. H., Hu, J., Rho, H. S., Xie, Z., Woodard, C., Neiswinger, J., Cooper, C., Shirley, M., Clark, H. M., Hu, S., Hwang, W., Seop Jeong, J., Wu, G., Lin, J., Gao, X., Ni, Q., Goel, R., Xia, S., Ji, H., ... Qian, J. (2013). Construction of human activity-based phosphorylation networks. Molecular Systems Biology, 9, [655]. https://doi.org/10.1038/msb.2013.12