Genevet, A.; (2010) Control of cell polarity and growth by the Hippo pathway in Drosophila. Doctoral thesis , UCL (University College London).

Abstract

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

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