UCLA

Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (MAPK) pathway. A role for non-mutated Raf in metastasis is also emerging, but the driving mechanisms remain unclear. Elevated expression of any of the three wildtype Raf family members (C, A or B) can drive metastasis. Here, we utilized an in vivo model to show that wildtype C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage dependent manner. Analysis of the transcriptomic and phospho-proteomic 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 C-Raf’s ability to form heterodimers with A-Raf and B-Raf are important for promoting metastasis. Taken together, these data identify wildtype C-Raf heterodimer signaling as a potential target for treating metastatic disease.