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 mitogen-activated 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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Takahashi M,Li Y,Dillon TJ,Kariya Y,Stork PJSdoi
10.1128/MCB.00132-17subject
Has Abstractpub_date
2017-09-12 00:00:00issue
19eissn
0270-7306issn
1098-5549pii
MCB.00132-17journal_volume
37pub_type
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