Article

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

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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.

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Acknowledgements

This work was supported by the NIH (CA131074 and CA184027) to RLE and a pilot grant from the Greenebaum Comprehensive Cancer Center (P30 CA134274).

Author information

Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Daniel Grun
    • , Gautam Adhikary
    •  & Richard L. Eckert
  2. Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Richard L. Eckert
  3. Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Richard L. Eckert
  4. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    • Richard L. Eckert

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Richard L. Eckert.