Disease implications of the Hippo/YAP pathway

Abstract

The Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Originally identified in Drosophila melanogaster, the core components of the Hippo pathway are highly conserved in mammals. The Hippo pathway can be modulated by a wide range of stimuli, including G protein-coupled receptor (GPCR) signaling, changes in the actin cytoskeleton, cell-cell contact, and cell polarity. When activated, the Hippo pathway functions as a tumor suppressor to limit cell growth. However, dysregulation by genetic inactivation of core pathway components or amplification or gene fusion of its downstream effectors results in increased cell proliferation and decreased apoptosis and differentiation. Unsurprisingly, this can lead to tissue overgrowth, tumorigenesis, and many other diseases.

Keywords: Hippo; TAZ; YAP; cancer; disease.

Figure 1. The Hippo signaling pathway

When the Hippo pathway is activated, MST1/2 in complex with SAV1 phosphorylate and activate LATS1/2 and MOB1. When activated, LATS1/2 phosphorylates YAP/TAZ, the primary effectors of the Hippo pathway. When phosphorylated, YAP/TAZ are sequestered in the cytoplasm or degraded. When YAP/TAZ are dephosphorylated, they translocate to the nucleus where they interact with TEAD1-4 to induce transcription and promote cell proliferation and inhibit apoptosis. Arrows and blunt ends indicate activation and inhibition, respectively.

Figure 2. Disease implications of the Hippo pathway

Dysregulation of the Hippo pathway has been implicated in a number of cancers and diseases throughout the body. Dysregulation may be due to genetic inactivation of core pathway components or amplification or gene fusion of its downstream effectors YAP and TAZ. Here we briefly summarize some of the diseases covered in this review.