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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-05-14

AUTHORS

Daniel Grun, Gautam Adhikary, Richard 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, angiogenesis, and tumor formation. More... »

PAGES

4711-4722

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41388-018-0290-4

DOI

http://dx.doi.org/10.1038/s41388-018-0290-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103931773

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29755126


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