VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells
| Autor: | Michael Klagsbrun, Ayumi Yoshida, Akio Shimizu, Hirotsugu Asano, Elena Geretti, Tetsuya Kadonosono, Misuzu Kurokawa Seo, Akiko Mammoto, Shinae Kondoh |
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| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Scaffold protein RHOA biology QH301-705.5 Cell growth Science RhoA Syx General Biochemistry Genetics and Molecular Biology VEGF-A Cell biology Downregulation and upregulation biology.protein Neuropilin Biology (General) Signal transduction General Agricultural and Biological Sciences PI3K/AKT/mTOR pathway CDK inhibitor Research Article Cancer |
| Zdroj: | Biology Open Biology Open, Vol 4, Iss 9, Pp 1063-1076 (2015) |
| ISSN: | 2046-6390 |
| Popis: | Neuropilin-1 (NRP1) has been identified as a VEGF-A receptor. DJM-1, a human skin cancer cell line, expresses endogenous VEGF-A and NRP1. In the present study, the RNA interference of VEGF-A or NRP1 suppressed DJM-1 cell proliferation. Furthermore, the overexpression of the NRP1 wild type restored shNRP1-treated DJM-1 cell proliferation, whereas NRP1 cytoplasmic deletion mutants did not. A co-immunoprecipitation analysis revealed that VEGF-A induced interactions between NRP1 and GIPC1, a scaffold protein, and complex formation between GIPC1 and Syx, a RhoGEF. The knockdown of GIPC1 or Syx reduced active RhoA and DJM-1 cell proliferation without affecting the MAPK or Akt pathway. C3 exoenzyme or Y27632 inhibited the VEGF-A-induced proliferation of DJM-1 cells. Conversely, the overexpression of the constitutively active form of RhoA restored the proliferation of siVEGF-A-treated DJM-1 cells. Furthermore, the inhibition of VEGF-A/NRP1 signaling upregulated p27, a CDK inhibitor. A cell-penetrating oligopeptide that targeted GIPC1/Syx complex formation inhibited the VEGF-A-induced activation of RhoA and suppressed DJM-1 cell proliferation. In conclusion, this new signaling pathway of VEGF-A/NRP1 induced cancer cell proliferation by forming a GIPC1/Syx complex that activated RhoA to degrade the p27 protein. |
| Databáze: | OpenAIRE |
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