Investigating the Role of Phosphorylation and Ubiquitylation Dependent Regulation of Hippo Signalling
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The Hippo Pathway is a highly conserved regulator of tissue growth and size determination, limiting the activity of the transcriptional co-activator Yorkie (Yki), which promotes proliferation and inhibits apoptosis. Hippo signalling integrates and transduces cell polarity and cell-cell adhesion inputs thereby responding to the state of tissue architecture. The transmembrane apical polarity protein Crumbs (Crb) controls the activity of Yki by regulating Expanded (Ex), a protein that promotes Hippo signalling through kinase-dependent and -independent mechanisms to robustly inhibit Yki activity. Crb plays a dual role in the regulation of Ex by controlling its apical localisation, facilitating Yki inhibition, and by promoting Ex degradation, thus activating Yki. Crb regulates the stability of Ex by stimulating a phosphorylation-dependent ubiquitylation and proteasomal degradation. Characterisation of the precise mechanisms by which Crb regulates Ex has been the focus of this thesis. Based on candidates identified by mass spectrometry and from literature, the Casein Kinase 1 (CK1) family of kinases, and the deubiquitylating enzyme (DUB) Usp2 have both been identified as novel regulators of Ex stability. CK1s promote Ex phosphorylation and degradation, acting as Ex inhibitors, while Usp2 promotes Ex function by promoting its stabilisation. Furthermore, in a screen to identify DUBs that regulate Drosophila adult wing size, CG10889 has been established as a novel regulator of growth that interacts with members of the Hippo pathway.
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