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


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.

SUBMITTER: Ta L 

PROVIDER: S-EPMC10711388 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Ta Lisa L   Tsai Brandon L BL   Deng Weixian W   Sha Jihui J   Varuzhanyan Grigor G   Tran Wendy W   Wohlschlegel James A JA   Carr-Ascher Janai R JR   Witte Owen N ON  

iScience 20231117 12


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 <i>in vivo</i> model to show that wild-type C-Raf overexpression can promote metastasis of immortalized prostate cells in a  ...[more]

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