title: Construction of human activity-based phosphorylation networks.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Newman
authors.forename: Jianfei
authors.initials: J
authors.lastname: Hu
authors.forename: Hee-Sool
authors.initials: HS
authors.lastname: Rho
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.forename: Crystal
authors.initials: C
authors.lastname: Woodard
authors.forename: John
authors.initials: J
authors.lastname: Neiswinger
authors.forename: Christopher
authors.initials: C
authors.lastname: Cooper
authors.forename: Matthew
authors.initials: M
authors.lastname: Shirley
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Clark
authors.forename: Shaohui
authors.initials: S
authors.lastname: Hu
authors.forename: Woochang
authors.initials: W
authors.lastname: Hwang
authors.forename: Jun Seop
authors.initials: JS
authors.lastname: Jeong
authors.forename: George
authors.initials: G
authors.lastname: Wu
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lin
authors.forename: Xinxin
authors.initials: X
authors.lastname: Gao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ni
authors.forename: Renu
authors.initials: R
authors.lastname: Goel
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Stephen
authors.initials: S
authors.lastname: Desiderio
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000465:Algorithms; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D001499:Bayes Theorem; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D040081:Protein Array Analysis; D060066:Protein Interaction Maps; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D017868:Cyclic AMP-Dependent Protein Kinases
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