The Hippo Signaling Network and Its Biological Functions

Abstract

Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and cell fate to control organ growth and regeneration. It promotes activation of the LATS kinases, which control gene expression by inhibiting the activity of the transcriptional coactivator proteins YAP and TAZ in mammals and Yorkie in Drosophila. Diverse upstream inputs, including both biochemical cues and biomechanical cues, regulate Hippo signaling and enable it to have a key role as a sensor of cells' physical environment and an integrator of growth control signals. Several components of this pathway localize to cell-cell junctions and contribute to regulation of Hippo signaling by cell polarity, cell contacts, and the cytoskeleton. Downregulation of Hippo signaling promotes uncontrolled cell proliferation, impairs differentiation, and is associated with cancer. We review the current understanding of Hippo signaling and highlight progress in the elucidation of its regulatory mechanisms and biological functions.

Keywords: Hippo; YAP; Yorkie; cancer; growth.

Fig. 1. Regulation of YAP and the Hippo core

A) Several biochemical mechanisms that regulate YAP proteins, as described in the text, are shown. Amino acids modified in human YAP1 are indicated. OGT = O-N-acetylglucosaminyl transferase. B) Sequence of interactions and phosphorylations involved in activation of LATS proteins, as described in the text, are shown. Hippo is activated by phosphorylation within its kinase domain, mediated by Hippo or Tao1 (1). Hippo phosphorylates Ser residues in its linker region, which recruits MOB, which is then phosphorylates by Hippo (2) Phosphorylated MOB recruits LATS (together with SAV and other pathway components not shown here), and LATS is then phosphorylated by Hippo, and also autophosphorylates to generate active LATS. This complex can be deactivated by SLMAP-mediated recruitment of the STRIPAK PP2a phosphatase complex (4); this recruitment is inhibited by SAV.

Fig. 2. Activation of core Hippo kinases

Several upstream factors that influence the activation of the core Hippo pathway kinases and YAP are shown, for details see text.

Fig 3. Cellular consequences of YAP activity

As described in the text, YAP activity has diverse consequences for cells during normal development and physiology. It often increases tissue growth by promoting cellular growth and cell proliferation, and inhibiting apoptosis. It also helps to maintain stem and progenitor cells in many tissues, while suppressing differentiation, but in other contexts can influence cell fate decisions or modify cellular phenotypes.