Regulation of Hippo signaling and cell proliferation by tension across tissues.

Mechanical tension across tissues is a major regulator of cell proliferation and plays an important role during development, organ growth, and tissue regeneration. Hippo pathway regulation of YAP is controlled by mechanical tension. When cells are at low density they experience high mechanical tension and YAP localizes to the nucleus and promotes cell proliferation. Conversely, cells at high density are under low tension, which causes YAP to exit the nucleus and stop proliferation. Transmission of tension across tissues requires cell-cell adhesion by cadherins, which act as a bridge to connect a cells contractile actin cytoskeleton to cadherins on neighboring cells. We showed that tension sensed at cell-cell junctions triggers activation of two LATS inhibitors called LIMD1 and TRIP6 that recruit LATS to cell-cell junctions and inhibit it. Our recent studies suggest that LIMD1 and TRIP6 can directly sense strain on f-actin filaments connected to cell-cell junctions. We are currently studying how LIMD1 and TRIP6 inhibit LATS only in the presence of mechanical strain. The lessons learned from these studies will likely have broad implications for how numerous other cellular pathways are regulated in response to mechanical strain.

Relevant Publicatons:

Ray S, DeSilva C, Dasgupta I, Mana-Capelli S, Cruz-Calderon N, McCollum D. The ability of the LIMD1 and TRIP6 LIM domains to bind strained f-actin is critical for their tension dependent localization to adherens junctions and association with the Hippo pathway kinase LATS1. Cytoskeleton (Hoboken). 2024. Epub 2024/03/01. doi: 10.1002/cm.21847. PubMed PMID: 38426816.