WW domain interactions regulate the Hippo tumor suppressor pathway

Abstract

The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the upstream inputs, downstream outputs and regulation of the whole cascade. Enrichment of the Hippo pathway components with WW domains and their cognate proline-rich interacting motifs provides a versatile platform for further understanding the mechanisms that regulate organ growth and tumorigenesis. Here, we review recently discovered mechanisms of WW domain-mediated interactions that contribute to the regulation of the Hippo signaling pathway in tumorigenesis. We further discuss new insights and future directions on the emerging role of such regulation.

Figure 1

ITCH regulates the Hippo pathway by degrading LATS1. The E3 ubiquitin ligase ITCH interacts with LATS1 by WW domain–PPxY motif-dependent manner leading to ubiquitination and protaesomal degradation of LATS1. This results in reduced YAPS127 phosphorylation, thus less cytoplasmic sequestration by binding to 14-3-3 protein, reduced YAP protaesomal degradation mediated by β-TRCP E3 ligase and consequently enhanced YAP translocation to the nucleus to mediate YAP dependent co-activation of TEAD-responsive genes, including those implicated in proliferation, anti-apoptosis and EMT. Upon activation of the pathway, ITCH–LATS1 interaction is enhanced leading to more efficient degradation of LATS1 attenuating its phosphorylation activity of YAP. This functional association might have a role in fine-tuning the outcome of the Hippo pathway and could be deregulated in specific setting such as in tumorigenesis.