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
Affiliations
Lisa Ta
Department of Molecular and Medical Pharmacology, University of California, Los Angeles; Los Angeles, CA 90095, USA
Brandon L. Tsai
Department of Human Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA
Weixian Deng
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA
Jihui Sha
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA
Grigor Varuzhanyan
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA
Wendy Tran
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA
James A. Wohlschlegel
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA
Janai R. Carr-Ascher
Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis, Sacramento, CA 95817, USA; Department of Orthopedic Surgery, University of California, Davis; Sacramento, CA 95817, USA
Owen N. Witte
Department of Molecular and Medical Pharmacology, University of California, Los Angeles; Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles; Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles; Los Angeles, CA 90095, USA; Corresponding author
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.
