YAP regulates cell mechanics by controlling focal adhesion assembly

TLDR

YAP/TAZ act as mechanosensing switches that respond to changes in extracellular matrix composition and mechanics, and their activity is regulated by a Hippo pathway hierarchy controlled by focal adhesions. The study investigates how cell spreading and RhoA GTPase activity drive focal adhesion formation through YAP to stabilize actin cytoskeleton anchorage. YAP’s co‑transcriptional activity activates genes encoding integrins and focal adhesion docking proteins, linking RhoA‑mediated spreading to focal adhesion assembly. Modulating YAP transcription alters cell mechanics, force generation, adhesion strength, shape, migration, and differentiation, establishing YAP as the key determinant of cell mechanics in response to ECM cues.

Abstract

Abstract Hippo effectors YAP/TAZ act as on–off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described by a hierarchical model in which elements of Hippo pathway are under the control of focal adhesions (FAs). Here we unveil the molecular mechanism by which cell spreading and RhoA GTPase activity control FA formation through YAP to stabilize the anchorage of the actin cytoskeleton to the cell membrane. This mechanism requires YAP co-transcriptional function and involves the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity leads to the modification of cell mechanics, force development and adhesion strength, and determines cell shape, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify this Hippo effector as the key determinant of cell mechanics in response to ECM cues.