The Hippo pathway in organ development, homeostasis, and regeneration

Abstract

The Hippo pathway is a universal governor of organ size, tissue homeostasis, and regeneration. A growing body of work has advanced our understanding of Hippo pathway regulation of cell proliferation, differentiation, and spatial patterning not only in organ development but also upon injury-induced regeneration. The pathway's central role in stem cell biology thus implicates its potential for therapeutic manipulation in mammalian organ regeneration. In this review, we survey recent literature linking the Hippo pathway to the development, homeostasis, and regeneration of various organs, including Hippo-independent roles for YAP, defined here as YAP functions that are not regulated by the Hippo pathway kinases LATS1/2.

Figure 1

Schematic of the mammalian Hippo pathway. The core Hippo pathway comprises the MST1/2 and LATS1/2 kinases, their cofactors SAV1 and MOB1A/B, transcriptional co-activators YAP and TAZ, and the TEAD1–4 family of transcription factors. When the pathway is active, the LATS kinases phosphorylate YAP/TAZ, which are sequestered and degraded in the cytoplasm. When the kinases are inactive, YAP/TAZ accumulate in the nucleus where they cooperate with TEAD factors to promote the expression of target genes. Core Hippo pathway components are shown in green, with the exception of YAP/TAZ, which are shown in pink. Recently identified interactors and regulators of the Hippo pathway described in this review are shown in purple. Dashed circles represent all possible complexes and interactions formed by Hippo components. The yellow arrow represents upregulation of the LATS-YAP interaction by CRB3. Abbreviations: PCBP = poly(rC)-binding protein; ERα = estrogen receptor alpha; DCAF = Ddb1-cullin4-associated-factor; DAG1 = dystroglycan; FAT4 = FAT tumor suppressor homolog 4; AMOTL1 = angiomotin-like 1; CRB3 = crumbs protein homolog 3.