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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 publication

DOI

10.1038/msb.2013.12

Type

Journal article

Journal

Mol Syst Biol

Publication Date

2013

Volume

9

Keywords

Algorithms, Amino Acid Sequence, B-Lymphocytes, Bayes Theorem, Cyclic AMP-Dependent Protein Kinases, Humans, Molecular Sequence Data, Phosphorylation, Protein Array Analysis, Protein Interaction Maps, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction, Tyrosine