The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal

Abstract

Precise control of organ size is crucial during animal development and regeneration. In Drosophila and mammals, studies over the past decade have uncovered a critical role for the Hippo tumour-suppressor pathway in the regulation of organ size. Dysregulation of this pathway leads to massive overgrowth of tissue. The Hippo signalling pathway is highly conserved and limits organ size by phosphorylating and inhibiting the transcription co-activators YAP and TAZ in mammals and Yki in Drosophila, key regulators of proliferation and apoptosis. The Hippo pathway also has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Emerging evidence shows that the Hippo pathway is regulated by cell polarity, cell adhesion and cell junction proteins. In this review we summarize current understanding of the composition and regulation of the Hippo pathway, and discuss how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration.

Figure 1

The Hippo pathway in Drosophila and mammals. Corresponding proteins in Drosophila (a) and mammals (b) are indicated by matching colours. Arrowed or blunted ends indicate activation or inhibition, respectively. Dashed lines indicate unknown mechanisms.

Figure 2

Mechanisms of YAP/TAZ/Yki inhibition by the Hippo pathway. (a) Phosphorylation-dependent cytoplasmic retention. Phosphorylation of YAP on Ser 127 by Lats1/2 induces 14-3-3 binding and cytoplasmic retention of YAP. The mechanism is conserved in TAZ and Yki. (b) Phosphorylation-independent cytoplasmic retention. Through WW domain–PPXY motif interactions, Yki binds to Mop, Ex, Hpo and Wts, and YAP/TAZ binds to AMOT family proteins. These interactions physically sequester Yki and YAP/TAZ in the cytoplasm. (c) Phosphorylation-induced ubiquitylation and degradation. Phosphorylation of YAP on Ser 381 by Lats1/2 primes further phosphorylation of YAP by CK1δ/ε, which induces interaction with SCFβ–TRCP and finally leads to YAP ubiquitylation and degradation. The mechanism is conserved in TAZ.

Figure 3

Mechanisms of the Hippo pathway in regulation of organ size and regeneration. Hexagons denote differentiated cells and circles denote stem/progenitor cells. Blue colour indicates wild-type and yellow colour indicates Hippo-pathway mutant cells. (a) Hippo pathway inactivation leads to stem/progenitor cell expansion in both cell-autonomous and non-autonomous manners. (b) Hippo pathway inactivation leads to cell cycle exit defects in some cellular contexts. (c) Hippo pathway mutations promote proliferation and decrease apoptosis in non-stem/progenitor cells. (d) Imbalance of Hippo pathway activity in neighbouring cells induces cell competition.