The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

Abstract

The Hippo pathway is an emerging tumour suppressor pathway that regulates cell proliferation, stem cell functions and organ size. The Hippo pathway transduces signals from diverse transmembrane inputs such as the cell adhesion and cell polarity receptors E-cadherin, FAT and Crumbs, as well as G protein-coupled receptors (GPCRs), through a kinase cascade that regulates the subcellular localization and activities of the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). YAP and TAZ promote cell proliferation and organ growth. Hyperactivation or overexpression of YAP in mouse models causes overgrowth of various organs and can lead to the development of cancer in the liver, skin and intestine. YAP and TAZ act as oncogenes and are hyperactivated or overexpressed with a high frequency in many common human cancers. YAP and TAZ promote multiple cancer cell phenotypes, including proliferation, migration and resistance to apoptosis. Direct or indirect inhibition of YAP and TAZ is a promising novel targeted approach for cancer therapy, and small-molecule modulators of the Hippo pathway have been discovered. Pharmacological modulation of YAP has been shown to be effective for reverting YAP-driven overgrowth phenotypes in mouse models. Further research is required to test whether small molecules targeting YAP and TAZ are active against human cancer cells and in mouse models that more accurately recapitulate the genetic defects of human tumours. By contrast, drugs that stimulate YAP and TAZ activity may be useful for stem cell expansion and tissue repair following injury. YAP is activated during the regeneration of the intestinal epithelium, and experimental activation of YAP promotes the capacity of the mouse heart to regenerate.