VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells
View/ Open
Author
Yoshida, Ayumi
Shimizu, Akio
Asano, Hirotsugu
Kadonosono, Tetsuya
Kondoh, Shinae Kizaka
Geretti, Elena
Seo, Misuzu Kurokawa
Published Version
https://doi.org/10.1242/bio.010918Metadata
Show full item recordCitation
Yoshida, Ayumi, Akio Shimizu, Hirotsugu Asano, Tetsuya Kadonosono, Shinae Kizaka Kondoh, Elena Geretti, Akiko Mammoto, Michael Klagsbrun, and Misuzu Kurokawa Seo. 2015. “VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells.” Biology Open 4 (9): 1063-1076. doi:10.1242/bio.010918. http://dx.doi.org/10.1242/bio.010918.Abstract
ABSTRACT 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582117/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:23473959
Collections
- HMS Scholarly Articles [17917]
Contact administrator regarding this item (to report mistakes or request changes)