Disease implication of hyper-Hippo signalling

Abstract

The Hippo signalling pathway regulates cellular proliferation, apoptosis and differentiation, thus exerting profound effects on cellular homeostasis. Inhibition of Hippo signalling has been frequently implicated in human cancers, indicating a well-known tumour suppressor function of the Hippo pathway. However, it is less certain whether and how hyperactivation of the Hippo pathway affects biological outcome in living cells. This review describes current knowledge of the regulatory mechanisms of the Hippo pathway, mainly focusing on hyperactivation of the Hippo signalling nexus. The disease implications of hyperactivated Hippo signalling have also been discussed, including arrhythmogenic cardiomyopathy, Sveinsson's chorioretinal atrophy, Alzheimer's disease, amyotrophic lateral sclerosis and diabetes. By highlighting the significance of disease-relevant Hippo signalling activation, this review can offer exciting prospects to address the onset and potential reversal of Hippo-related disorders.

Keywords: Alzheimer's disease; Hippo pathway; Sveinsson's chorioretinal atrophy; amyotrophic lateral sclerosis; arrhythmogenic cardiomyopathy; diabetes.

Figure 1.

Models of Hippo pathway in fly and mammals. A simplified version of Hippo pathway regulation is shown here. In both Drosophila and mammals, when Yki/YAP/TAZ is relieved from inhibition through phosphorylation-dependent or independent mechanisms, its nuclear translocation then drives target gene expression in regulation of cellular proliferation, apoptosis and differentiation. The phosphorylation mechanism relies on the core kinase cascade including Hpo/MST, Wts/LATS, Sav/SAV1 and Mats/MOB1. In Drosophila, the FERM domain protein Ex has been shown to physically associate with Yki and block its nuclear translocation. Similarly, in mammals, the adherens protein AMOT and CRB3 complex inhibit target gene expression via sequestering YAP/TAZ in cytoplasm.

Figure 2.

Intrinsic Hippo activation by Drosophila HLH proteins. Depletion of Drosophila ID protein results in elevated Drosophila E protein. The high levels of E protein activate ex transcription through binding to the E-box sites in the cis-regulatory element, thereby activating the Hippo pathway. The hyperactivated Hippo pathway prevents cellular proliferation and survival, leading to the elimination of misspecified progenitor cells.