Filling out the Hippo pathway

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Abstract
Studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelia. Although this pathway is currently poorly characterized in mammals, several components of the Hippo pathway appear to function as tumour suppressors. The protein Fat, originally discovered in D. melanogaster as the founding member of a subfamily of genes called protocadherins, has been newly identified as an upstream regulator of the Hippo pathway. The data suggest that Fat increases Hippo activity by two mechanisms: it modulates Hippo activity through phosphorylation and stabilizes the Warts protein (a central kinase of the Hippo signal transduction pathway). Two recent reports have identified a new transcriptional target downstream of the Hippo pathway in D. melanogaster that can promote tissue growth and inhibit apoptosis: the microRNA bantam. However, it remains unclear how bantam promotes cell proliferation and whether the mechanism(s) is conserved in mammals. In flies and mammals, Hippo signalling promotes apoptosis in response to irradiation. Recent work in D. melanogaster suggests that p53 is responsible for the activation of Hippo following irradiation, and that members of the Ras association family can temper this response. Loss of Hippo signalling allows cells in the developing fly to outcompete and eliminate neighbouring wild-type cells. This phenomenon is known as supercompetition. The mechanism(s) that enables Hippo-mutant cells to act as 'supercompetitors' remains unclear. Two unresolved questions pertaining to the Hippo pathway are: do extracellular ligands regulate Hippo activity by binding to Fat? And does the supercompetition phenotype of Hippo mutants contribute to mammalian tumorigenesis?