NRP-1 interacts with GIPC1 and ?6/?4-integrins to increase YAP1/?Np63?-dependent epidermal cancer stem cell survival.

We have identified an epidermal cancer stem (ECS) cell population that drives formation of rapidly growing and highly invasive and vascularized tumors. VEGF-A and neuropilin-1 (NRP-1) are highly expressed in ECS cell tumors and VEGF-A/NRP-1 interaction is required for ECS cell survival and tumor vascularization. We now identify a novel ...
signaling cascade that is triggered by VEGF-A/NRP-1. We show that NRP-1 forms a complex with GIPC1 and ?6/?4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/?Np63? to enhance ECS cell survival, invasion, and angiogenesis. Loss of NRP-1, GIPC1, ?6/?4-integrins, YAP1, or ?Np63? reduces these responses. Moreover, restoration of constituently active YAP1 or ?Np63? in NRP-1 null cells restores the ECS cell phenotype. Tumor xenograft experiments show that NRP-1 knockout ECS cells form small tumors characterized by reduced vascularization as compared to wild-type cells. The NRP-1 knockout tumors display signaling changes consistent with a role for the proposed signaling cascade. These studies suggest that VEGF-A interacts with NRP-1 and GIPC1 to regulate ?6/?4-integrin, FAK, Src, PI3K/PDK1, LATS1 signaling to increase YAP1/?Np63? accumulation to drive ECS cell survival, angiogenesis, and tumor formation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Line, Cell Line, Tumor, Cell Survival, Epidermal Cells, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Integrin alpha6beta4, Mice, Mice, Knockout, Neoplastic Stem Cells, Neovascularization, Pathologic, Neuropilin-1, Phosphoproteins, Signal Transduction
Oncogene
Date: Dec. 01, 2017
Download Curated Data For This Publication
219648
Switch View:
  • Interactions 3