The role of the Hippo pathway in human disease and tumorigenesis

Abstract

Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.

Keywords: Apoptosis; Cancer; Hippo signaling; YAP.

Figure 1

Schematic of the core Hippo signaling pathway in Drosophila and humans. Human molecules are in bold, Drosophila molecules in parentheses. Regulators, which act to restrict YAP/TAZ/Yki activation, are blue, and downstream transcriptional effectors are red.

Figure 2

Schematic of cancer related pathways and processes that input into the Hippo pathway. Core mammalian Hippo pathway components are in black, and additional cancer related molecular pathways are in red.