NRP-1 interacts with GIPC1 and SYX to activate p38 MAPK signaling and cancer stem cell survival

NRP-1 interacts with GIPC1 and SYX to activate p38 MAPK signaling and cancer stem cell survival

Abstract

Epidermal cancer stem cells (ECS cells) comprise a limited population of cells that form aggressive, rapidly growing, and highly vascularized tumors. VEGF‐A/NRP‐1 signaling is a key driver of the ECS cell phenotype and aggressive tumor formation. However, relatively less is known regarding the downstream events following VEGF‐A/NRP‐1 interaction. In the present study, we show that VEGF‐A/NRP‐1, GIPC1, and Syx interact to increase RhoA‐dependent p38 MAPK activity to enhance ECS cell spheroid formation, invasion, migration, and angiogenic potential. Inhibition or knockdown of NRP‐1, GIPC1 or Syx attenuates RhoA and p38 activity to reduce the ECS cell phenotype, and NRP‐1 knockout, or pharmacologic inhibition of VEGF‐A/NRP‐1 interaction or RhoA activity, reduces p38 MAPK activity and tumor growth. Moreover, expression of wild‐type or constitutively‐active RhoA, or p38, in NRP1‐knockout cells, restores p38 activity and the ECS cell phenotype. These findings suggest that NRP‐1 forms a complex with GIPC1 and Syx to activate RhoA/ROCK‐dependent p38 activity to enhance the ECS cell phenotype and tumor formation.

Authors: Daniel Grun PhD, Gautam Adhikary PhD, Richard L. Eckert PhD

Influence Factor: 3.85

Citation: Mol Carcinog 58, 488-499 (2019).

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