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

Year: 2023
Type: article
Abstract: 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.
Source: iScience
DOI: 10.1016/j.isci.2023.108480
Authors: Lisa Ta, Brandon L. Tsai, Weixian Deng, Jihui Sha, Grigor Varuzhanyan, Wendy Tran, James A. Wohlschlegel, Janai R. Carr-Ascher, Owen N. Witte
Institutions: University of California, Los Angeles, University of California Davis Medical Center, University of California, Davis, Parker Institute for Cancer Immunotherapy, Broad Center, UCLA Jonsson Comprehensive Cancer Center
Language: English
Open Access status: gold
Estimated APC paid: $3,150
Funders: Concern Foundation, National Institutes of Health, University of California, Los Angeles, University of California, Davis, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, Allogene Therapeutics
OpenAlex ID: W4388751880
FWCI: 0.089
Cites: 73
Cited by: 1
Related to: 10