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Systematic discovery of in vivo phosphorylation networks

Item Type:Article
Title:Systematic discovery of in vivo phosphorylation networks
Creators Name:Linding, R., Jensen, L.J., Ostheimer, G.J., van Vugt, M.A., Jorgensen, C., Miron, I.M., Diella, F., Colwill, K., Taylor, L., Elder, K., Metalnikov, P., Nguyen, V., Pasculescu, A., Jin, J., Park, J.G., Samson, L.D., Woodgett, J.R., Russell, R.B., Bork, P., Yaffe, M.B. and Pawson, T.
Abstract: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.
Keywords:CELLBIO, Binding Sites, CDC2 Protein Kinase, Cell Cycle Proteins, Computational Biology, DNA Damage, DNA Repair Enzymes, DNA-Binding Proteins, Glycogen Synthase Kinase 3, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Proteomics, Repressor Proteins, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins
Publisher:Cell Press
Page Range:1415-1426
Date:29 June 2007
Official Publication:https://doi.org/10.1016/j.cell.2007.05.052
PubMed:View item in PubMed

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