Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223025579 |
| _version_ | 1827582064192389120 |
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| author | Lisa Ta Brandon L. Tsai Weixian Deng Jihui Sha Grigor Varuzhanyan Wendy Tran James A. Wohlschlegel Janai R. Carr-Ascher Owen N. Witte |
| author_facet | Lisa Ta Brandon L. Tsai Weixian Deng Jihui Sha Grigor Varuzhanyan Wendy Tran James A. Wohlschlegel Janai R. Carr-Ascher Owen N. Witte |
| author_sort | Lisa Ta |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T22:45:11Z |
| format | Article |
| id | doaj.art-50c08eec40e64d8eaf3c2bad01473b66 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-08T22:45:11Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-50c08eec40e64d8eaf3c2bad01473b662023-12-17T06:40:57ZengElsevieriScience2589-00422023-12-012612108480Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasisLisa Ta0Brandon L. Tsai1Weixian Deng2Jihui Sha3Grigor Varuzhanyan4Wendy Tran5James A. Wohlschlegel6Janai R. Carr-Ascher7Owen N. Witte8Department of Molecular and Medical Pharmacology, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Human Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USADepartment 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, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223025579BiochemistryMolecular biologyCancerProteomicsTranscriptomics |
| spellingShingle | Lisa Ta Brandon L. Tsai Weixian Deng Jihui Sha Grigor Varuzhanyan Wendy Tran James A. Wohlschlegel Janai R. Carr-Ascher Owen N. Witte Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis iScience Biochemistry Molecular biology Cancer Proteomics Transcriptomics |
| title | Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis |
| title_full | Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis |
| title_fullStr | Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis |
| title_full_unstemmed | Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis |
| title_short | Wild-type C-Raf gene dosage and dimerization drive prostate cancer metastasis |
| title_sort | wild type c raf gene dosage and dimerization drive prostate cancer metastasis |
| topic | Biochemistry Molecular biology Cancer Proteomics Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223025579 |
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