NRP-1 interacts with GIPC1 and α6/β4-integrins to increase YAP1/∆Np63α-dependent epidermal cancer stem cell survival.

Oncogene
Daniel GrunRichard L Eckert

Abstract

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 α6/β4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/∆Np63α to enhance ECS cell survival, invasion, and angiogenesis. Loss of NRP-1, GIPC1, α6/β4-integrins, YAP1, or ∆Np63α reduces these responses. Moreover, restoration of constituently active YAP1 or ∆Np63α 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 α6/β4-integrin, FAK, Src, PI3K/PDK1, LATS1 signaling to increase YAP1/∆Np63α accumulation to drive ECS cell survival, an...Continue Reading

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Citations

Nov 21, 2018·Molecular Carcinogenesis·Daniel GrunRichard L Eckert
Jul 10, 2019·Cancer Biomarkers : Section a of Disease Markers·Yong-Yao GuZhi-Gang Peng
Oct 18, 2018·Science Signaling·Ameer L Elaimy, Arthur M Mercurio
Jun 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ameer L ElaimyArthur M Mercurio
Sep 13, 2020·Journal of Cell Science·Matthew L FisherAlea A Mills
Jan 27, 2019·International Journal of Molecular Sciences·Arthur M Mercurio
Dec 29, 2020·Neoplasia : an International Journal for Oncology Research·Tasmia AhmedNam Y Lee
Feb 28, 2021·The Journal of Pathology·Zuzana PokornáPhilip J Coates
May 19, 2021·Molecular Carcinogenesis·McKayla MickleRichard L Eckert

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Methods Mentioned

BETA
immunoprecipitation
xenograft
FCS

Software Mentioned

ImageJ

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