Systematic Discovery of In Vivo Phosphorylation Networks

Rune Linding, Lars Juhl Jensen, Gerard J. Ostheimer, Marcel A.T.M. van Vugt, Claus Jørgensen, Ioana M. Miron, Francesca Diella, Karen Colwill, Lorne Taylor, Kelly Elder, Pavel Metalnikov, Vivian Nguyen, Adrian Pasculescu, Jing Jin, Jin Park, Leona D. Samson, James R. Woodgett, Robert B B. Russell, Peer Bork, Michael B. Yaffe & 1 others Tony Pawson

Research output: Contribution to journalArticle

519 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1415-1426
Number of pages12
JournalCell
Volume129
Issue number7
DOIs
StatePublished - Jun 29 2007
Externally publishedYes

Fingerprint

Phosphorylation
Phosphotransferases
Substrate Specificity
Substrates
Glycogen Synthase Kinase 3
Phosphoproteins
Proteome
Protein Kinases
DNA Damage
Automatic teller machines
Scaffolds
DNA
Proteins

Keywords

  • CELLBIO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Linding, R., Jensen, L. J., Ostheimer, G. J., van Vugt, M. A. T. M., Jørgensen, C., Miron, I. M., ... Pawson, T. (2007). Systematic Discovery of In Vivo Phosphorylation Networks. Cell, 129(7), 1415-1426. https://doi.org/10.1016/j.cell.2007.05.052

Systematic Discovery of In Vivo Phosphorylation Networks. / Linding, Rune; Jensen, Lars Juhl; Ostheimer, Gerard J.; van Vugt, Marcel A.T.M.; Jørgensen, Claus; Miron, Ioana M.; Diella, Francesca; Colwill, Karen; Taylor, Lorne; Elder, Kelly; Metalnikov, Pavel; Nguyen, Vivian; Pasculescu, Adrian; Jin, Jing; Park, Jin; Samson, Leona D.; Woodgett, James R.; Russell, Robert B B.; Bork, Peer; Yaffe, Michael B.; Pawson, Tony.

In: Cell, Vol. 129, No. 7, 29.06.2007, p. 1415-1426.

Research output: Contribution to journalArticle

Linding, 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, J, Samson, LD, Woodgett, JR, Russell, RBB, Bork, P, Yaffe, MB & Pawson, T 2007, 'Systematic Discovery of In Vivo Phosphorylation Networks', Cell, vol. 129, no. 7, pp. 1415-1426. https://doi.org/10.1016/j.cell.2007.05.052
Linding R, Jensen LJ, Ostheimer GJ, van Vugt MATM, Jørgensen C, Miron IM et al. Systematic Discovery of In Vivo Phosphorylation Networks. Cell. 2007 Jun 29;129(7):1415-1426. https://doi.org/10.1016/j.cell.2007.05.052
Linding, Rune ; Jensen, Lars Juhl ; Ostheimer, Gerard J. ; van Vugt, Marcel A.T.M. ; Jørgensen, Claus ; Miron, Ioana M. ; Diella, Francesca ; Colwill, Karen ; Taylor, Lorne ; Elder, Kelly ; Metalnikov, Pavel ; Nguyen, Vivian ; Pasculescu, Adrian ; Jin, Jing ; Park, Jin ; Samson, Leona D. ; Woodgett, James R. ; Russell, Robert B B. ; Bork, Peer ; Yaffe, Michael B. ; Pawson, Tony. / Systematic Discovery of In Vivo Phosphorylation Networks. In: Cell. 2007 ; Vol. 129, No. 7. pp. 1415-1426.
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