G-Protein Coupled Receptors Engage the Mammalian Hippo pathway through F-Actin F-Actin, assembled in response to Galpha

• Published in: BioEssays Vol. 35; no. 5; pp. 430 - 435
• Main Authors: Regué, Laura, Mou, Fan, Avruch, Joseph
• Format: Journal Article
• Language: English
• Published: 01.03.2013
• ISSN: 0265-9247; 1521-1878
• DOI: 10.1002/bies.201200163

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell-cell contact or determine epithelial cell polarity which, in a tissue specific manner, use intracellular complexes containing FERM domain and actin-binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha 12/13 such as the Protease Activated Receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F-)actin. Morever, cell architectures that promote F-actin assembly per se also activate YAP by kinase-dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells.