Control of cell polarity and growth by the Hippo pathway in Drosophila

The Hippo (Hpo) signalling pathway comprises the kinases Hpo and Warts (Wts), \nthe adaptors Salvador and Mats, the cytoskeletal proteins Expanded (Ex) and Merlin \n(Mer), the atypical cadherin Fat and the transcriptional co-factor Yorkie (Yki). This \npathway has been shown to restrict tissue size through the control of cell division and \napoptosis during development in Drosophila. \nIn addition to their well-characterised overproliferation phenotype, adult epithelial \ncells mutant for the kinases Hpo and Wts present a hypertrophy of the apical domain. I \nexamined the molecular basis of this apical hypertrophy and its impact on cell \nproliferation. In the wing imaginal disc epithelium, I observe increased staining for \nmembers of the apical polarity complexes aPKC and Crumbs as well as adherens \njunction components when Hpo activity is compromised, while baso-lateral markers are \nnot affected. This increase in apical proteins is correlated with a hypertrophy of the \napical domain and adherens junctions. Interestingly however, while the polarity \ndeterminant Crumbs is required for the accumulation of apical proteins, this does not \nappear to significantly contribute to the overproliferation defect elicited by loss of Hpo \nsignalling. Therefore, the Hpo pathway controls growth and apical domain size via \ndistinct mechanisms. \nIn collaboration with the Thompson lab (CRUK LRI) we identified the WWdomain- \ncontaining protein Kibra (Kib) as a new member of the Hpo pathway. Kib, \nwhich colocalises and physically interacts with Mer and Ex, also promotes the Mer/Ex \nassociation. Furthermore, the Kib/Mer interaction is conserved in human cells. Loss of \nkib induces a hpo-like phenotype and genetic experiments place it upstream of the core \nkinase cassette. Finally, Kib binds to Wts and kib depletion in tissue culture cells \ninduces a marked reduction in Yki phosphorylation without affecting the Yki/Wts \ninteraction. My work therefore suggests that Kib is part of an apical scaffold that \npromotes Hpo pathway activity.