Systematic discovery of in vivo phosphorylation networks.

TitleSystematic discovery of in vivo phosphorylation networks.
Publication TypeJournal Article
Year of Publication2007
AuthorsLinding, R, Jensen, LJ, Ostheimer, GJ, van Vugt, MATM, Jørgensen, C, Miron, IM, Diella, F, Colwill, K, Taylor, L, Elder, K, Metalnikov, P, Nguyen, V, Pasculescu, A, Jin, J, Park, JGyoon, Samson, LD, Woodgett, JR, Russell, RB, Bork, P, Yaffe, MB, Pawson, T
Date Published2007 Jun 29
KeywordsBinding Sites, CDC2 Protein Kinase, Cell Cycle Proteins, Computational Biology, DNA Damage, DNA Repair Enzymes, DNA-Binding Proteins, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Proteomics, Repressor Proteins, Signal Transduction, Software, Transcription Factors, Tumor Suppressor Proteins

Protein kinases control cellular decision processes by phosphorylating specific substrates. Thousands of in vivo phosphorylation sites have been identified, mostly by proteome-wide mapping. However, systematically matching these sites to specific kinases is presently infeasible, due to limited specificity of consensus motifs, and the influence of contextual factors, such as protein scaffolds, localization, and expression, on cellular substrate specificity. We have developed an approach (NetworKIN) that augments motif-based predictions with the network context of kinases and phosphoproteins. The latter provides 60%-80% of the computational capability to assign in vivo substrate specificity. NetworKIN pinpoints kinases responsible for specific phosphorylations and yields a 2.5-fold improvement in the accuracy with which phosphorylation networks can be constructed. Applying this approach to DNA damage signaling, we show that 53BP1 and Rad50 are phosphorylated by CDK1 and ATM, respectively. We describe a scalable strategy to evaluate predictions, which suggests that BCLAF1 is a GSK-3 substrate.

Alternate JournalCell
PubMed ID17570479
PubMed Central IDPMC2692296
Grant List12043 / / Canadian Institutes of Health Research / Canada
U54 CA112967-03 / CA / NCI NIH HHS / United States
U54-CA112967-03 / CA / NCI NIH HHS / United States