Mechanobiology of the Hippo–YAP Signaling Network

Cells are not only biochemical machines but also mechanical entities, which experience physical cues ranging from extracellular matrix (ECM) stiffness to cytoskeletal tension and intercellular adhesion. The Hippo signaling network is a key interpreter of these cues, responding to multiple, intertwined inputs including filamentous actin (F-actin) abundance and architecture, actomyosin contractility, integrin-focal adhesion signaling, junctional complexes, and nuclear mechanics, to modulate Yorkie (Yki)/Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) activity and ultimately cell fate, organ growth, and tissue homeostasis. Mechanoregulation can be Hippo-dependent (via regulation of Wts/LATS kinases) or Hippo-independent. Hippo signaling and YAP/TAZ also feed back on mechanics, modulating F-actin levels, focal adhesions, and actomyosin contractility. Links between tissue mechanics and Hippo signaling have important physiological roles in development and homeostasis. Conversely, in disease states including cancer and fibrosis altered mechanics can chronically activate YAP/TAZ, creating feedforward tissue stiffening and maladaptive remodeling. Understanding Hippo mechanobiology can thus inform strategies that restore balance between adaptive and pathological responses to tissue mechanics.