iScience (Dec 2023)

Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis

  • Lisa Ta,
  • Brandon L. Tsai,
  • Weixian Deng,
  • Jihui Sha,
  • Grigor Varuzhanyan,
  • Wendy Tran,
  • James A. Wohlschlegel,
  • Janai R. Carr-Ascher,
  • Owen N. Witte

Journal volume & issue
Vol. 26, no. 12
p. 108480

Abstract

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Summary: Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway. A role for non-mutated Raf in metastasis is also emerging, but the key mechanisms remain unclear. Elevated expression of any of the three wild-type Raf family members (C, A, or B) can drive metastasis. We utilized an in vivo model to show that wild-type C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage-dependent manner. Analysis of the transcriptomic and phosphoproteomic landscape indicated that C-Raf-driven metastasis is accompanied by upregulated MAPK signaling. Use of C-Raf mutants demonstrated that the dimerization domain, but not its kinase activity, is essential for metastasis. Endogenous Raf monomer knockouts revealed that C-Raf’s ability to form dimers with endogenous Raf molecules is important for promoting metastasis. These data identify wild-type C-Raf heterodimer signaling as a potential target for treating metastatic disease.

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