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

被引：0

作者：

Ta, Lisa ^{[1
]}

Tsai, Brandon L. ^{[2
]}

Deng, Weixian ^{[3
]}

Sha, Jihui ^{[3
]}

Varuzhanyan, Grigor ^{[4
]}

Tran, Wendy ^{[4
]}

Wohlschlegel, James A. ^{[3
]}

Carr-Ascher, Janai R. ^{[5
,6
]}

Witte, Owen N. ^{[1
,4
,7
,8
,9
,10
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[5] Univ Calif Davis, Dept Internal Med, Div Hematol Oncol, Sacramento, CA 95817 USA

[6] Univ Calif Davis, Dept Orthoped Surg, Sacramento, CA 95817 USA

[7] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Eli & Edythe Broad, Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, Parker Inst Canc Immunotherapy, Los Angeles, CA 90095 USA

来源：

ISCIENCE | 2023年 / 26卷 / 12期

基金：

美国国家卫生研究院;

关键词：

SIGNALING PATHWAYS; KINASE-ACTIVITY; BRAF; PHOSPHORYLATION; INHIBITORS; EXPRESSION; CRAF; ACTIVATION; MECHANISMS; SUFFICIENT;

D O I：

10.1016/j.isci.2023.108480

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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