p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity

Area of Science:

• Molecular biology
• Cancer genetics
• Cell signaling

Background:

• ARHGAP35 gene encodes p190A RhoGAP, implicated in cancer.
• Its mutation spectrum suggests a tumor-suppressor function.
• Loss of heterozygosity for ARHGAP35 is observed in human tumors.

Purpose of the Study:

• Investigate the tumor-suppressor capacities of p190A RhoGAP and its paralog p190B in epithelial cells.
• Elucidate the mechanism by which these proteins regulate cell proliferation and cancer development.

Main Methods:

• Analysis of loss of heterozygosity in human tumors.
• Assessment of contact inhibition of cell proliferation (CIP) assays.
• Unbiased mRNA sequencing.
• Western blotting and kinase assays to study signaling pathways.

Main Results:

• p190A and p190B are essential for maintaining CIP in epithelial cells.
• These proteins modulate Hippo pathway gene expression.
• p190A and p190B repress YAP-TEAD transcription via LATS kinase activation and Rho-ROCK pathway inhibition.
• Loss of a single p190 paralog perturbs CIP and causes YAP nuclear translocation.

Conclusions:

• p190A and p190B RhoGAP proteins play a critical role in regulating epithelial cell proliferation through the Hippo pathway.
• Dysregulation of ARHGAP35 contributes to cancer by impairing contact inhibition.
• These findings reveal a novel tumor-suppressor mechanism for ARHGAP35.