Regulation of the Hippo pathway in cancer biology

Abstract

The Hippo tumor suppressor pathway, which is well conserved from Drosophila to humans, has emerged as the master regulator of organ size, as well as major cellular properties, such as cell proliferation, survival, stemness, and tissue homeostasis. The biological significance and deregulation of the Hippo pathway in tumorigenesis have received a surge of interest in the past decade. In the current review, we present the major discoveries that made substantial contributions to our understanding of the Hippo pathway and discuss how Hippo pathway components contribute to cellular signaling, physiology, and their potential implications in anticancer therapeutics.

Keywords: Cancer; Hippo pathway; TEAD; Therapeutic target; YAP/TAZ.

Fig. 1

Core Hippo pathway components in Drosophila and mammals. In Drosophila (left), Hippo (Hpo) and Misshapen (Msn) kinase phosphorylate and activate Warts (Wts) kinase, which in turn inactivate the transcriptional co-activator Yorkie (Yki). Phosphorylation of Yki leads to cytoplasmic retention via a 14-3-3 interaction. Upon Hippo pathway inactivation, dephosphorylated Yki translocates to the nucleus and binds the transcription factor Scalloped (Sd) to induce gene expression involved in cell proliferation and anti-apoptosis. In mammals (right), the core Hippo pathway components are evolutionarily conserved. MST1/2 kinase phosphorylates LATS1/2, which in turn phosphorylates and inhibits YAP/TAZ. Phosphorylation of YAP/TAZ leads to cytoplasmic sequestration and proteasomal degradation

Fig. 2

Regulators and regulations of the Hippo pathway. Hippo pathway components in mammals are shown in various colors. Pointed arrows indicate activation, and blunt-ended lines indicate inhibition. Hippo cascade kinases are shown in red and inhibitory regulators of YAP/TAZ activity are shown in blue. a Hippo pathway is regulated by cell polarity (Crumbs, DACH1–FAT4) and cell–cell junctions (adherens junction, tight junction). AMOT angiomotin, AJ adherens junction, CRB Crumbs homolog, DACH1 Dachous-1, FRMD6 FERM domain-containing protein 6, LATS large tumor suppressor homolog, MST mammalian STE20-like protein kinase, NF2 neurofibromin 2 (also known as Merlin), PTPN14 protein tyrosine phosphatase, non-receptor type 14, SCRIB scribbled planar-cell polarity protein, TAZ transcriptional co-activator with PDZ-binding motif, TJ tight junction, VGLL4 vestigial-like protein 4, YAP Yes-associated protein, ZO zona occludens protein. b Hippo pathway is regulated by extracellular ligands, stress responses, and mechanotransduction. AMPK 5′ AMP-activated protein kinase, APC adenomatous polyposis coli, β-TRCP β-transducin repeat-containing E3 ubiquitin protein ligase, ECM extracellular matrix, GPCR G protein-coupled receptor, Rho Ras homolog gene family, ROCK Rho-associated protein kinase

Fig. 3

Putative targets for therapeutic intervention in the Hippo pathway. Summary of the positive and negative regulators of Hippo kinases and YAP/TAZ, respectively. Activating components’ upstream of YAP/TAZ is in green, and inhibitory components are in red