Phosphorylation of the C-Raf N region promotes Raf dimerization

Maho Takahashi, Yanping Li, Tara J. Dillon, Yumi Kariya, Philip Stork

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop, and the other lies within the N-terminal acidic region (N region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341) and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylations of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization. One of these phosphorylations (phospho- Y341) is required for C-Raf dimerization, and this action can be replicated by phosphomimetic mutants both in vivo and in vitro. The role of the phosphorylation of Y341 in promoting Raf dimerization is distinct from its well-known function in facilitating S338 phosphorylation. In Ras mutant pancreatic cancer cell lines, the phosphorylation and dimerization of C-Raf are basally elevated. Dimerization is thought to contribute to their elevated growth rate through their activation of the mitogenactivated protein (MAP) kinase (extracellular signal-regulated kinase [ERK]) signaling cascade. Blocking the tyrosine phosphorylation of C-Raf with Src family inhibitors blocks growth, basal dimerization, and ERK activation in these cells. We suggest that the kinases mediating C-Raf Y341 phosphorylation are potential candidate drug targets in selected Ras-dependent cancers.

Original languageEnglish (US)
Article numbere00132-17
JournalMolecular and Cellular Biology
Volume37
Issue number19
DOIs
StatePublished - Oct 1 2017

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Dimerization
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Serine
Tyrosine
raf Kinases
Growth Inhibitors
Monomeric GTP-Binding Proteins
Pancreatic Neoplasms
Protein Kinases
Protein Isoforms
Phosphotransferases
Cell Line
Growth

Keywords

  • B-Raf
  • C-Raf
  • Dimerization
  • Extracellular signalregulated kinase (ERK)
  • Phosphorylation
  • Ras

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Phosphorylation of the C-Raf N region promotes Raf dimerization. / Takahashi, Maho; Li, Yanping; Dillon, Tara J.; Kariya, Yumi; Stork, Philip.

In: Molecular and Cellular Biology, Vol. 37, No. 19, e00132-17, 01.10.2017.

Research output: Contribution to journalArticle

Takahashi, Maho ; Li, Yanping ; Dillon, Tara J. ; Kariya, Yumi ; Stork, Philip. / Phosphorylation of the C-Raf N region promotes Raf dimerization. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 19.
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