The role of extracellular biophysical cues in modulating the Hippo-YAP pathway

Abstract

The Hippo signaling pathway plays an essential role in adult-tissue homeostasis and organ-size control. In Drosophila and vertebrates, it consists of a highly conserved kinase cascade, which involves MST and Lats that negatively regulate the activity of the downstream transcription coactivators, YAP and TAZ. By interacting with TEADs and other transcription factors, they mediate both proliferative and antiapoptotic gene expression and thus regulate tissue repair and regeneration. Dysregulation or mutation of the Hippo pathway is linked to tumorigenesis and cancer development. Recent studies have uncovered multiple upstream inputs, including cell density, mechanical stress, G-protein-coupled receptor (GPCR) signaling, and nutrients, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway as effector of these biophysical cues and its potential implications in tissue homeostasis and cancer. [BMB Reports 2017; 50(2): 71-78].

Fig. 1

Regulation of the Hippo-YAP pathway by extracellular biophysical cues. Mechanical stress inhibits Lats1/2 kinase activity via Rho GTPase and the actin cytoskeleton. GPCR signaling can either activate or inhibit YAP/TAZ activity through the coupled Gα protein. Cellular junction and cell polarity modulate the Hippo pathway. Nutrient signaling modulates the core Hippo kinase and YAP activity through AMPK. YAP/TAZ activity is involved in amino-acid induced mTORC1 activation.