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 aluminum lotion knockdown of GIPC1 or Syx reduced active RhoA and DJM-1 cell Canvas Mesh Athletic Running Shoes 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.