Mechanisms of Hippo pathway regulation

Abstract

The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

“…The Hippo pathway is the major regulator of YAP activity (60,61). Upstream signals that activate Hippo (and inactivate YAP) include extracellular soluble factors via G protein-coupled receptors, mechanotransduction, cell-cell contact, and polarity (28,62), including apical polarity complexes such as Crb3 (63).…”

Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

“…binding predominantly SV40 GT-IIC (5′-GGAATG-3′) and Muscle-CAT (5′-CATTCCT-3′) (13) elements and play critical roles in cell proliferation, lineage differentiation, and tumor formation (11,14,15). Of the 4 members of the TEAD family, Tead1 is the most abundant in the heart and plays a nonredundant role in cardiac development, as germline deletion of Tead1 led to cardiac hypoplasia and embryonic lethality at E11.5 (16).…”

Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP

“…Many upstream signals of YAP and TAZ have been identified [21]. Most notably, cell contact inhibition, mechanotransduction, cellular energy status, and mitogens in serum can potently regulate YAP activity [15,[22][23][24][25][26][27].…”