Kulaberoglu, Y; (2017) The functional characterisation of MOB1-regulated Hippo core cassette kinase signalling. Doctoral thesis , UCL (University College London).

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Abstract

The Hippo tumour suppressor pathway regulates tissue growth by co-ordinating cell death, proliferation and differentiation. The central Hippo core cassette consists of MST1/2, LATS1/2, NDR1/2 and MOB1, with recent studies of MOB1 knockout mice indicating MOB1 functions as the central hub of Hippo signalling. However, it has remained unknown which interactions of MOB1 with the Hippo core cassette kinases MST1/2, LATS1/2 and NDR1/2 are required for normal life and tumour suppression. Therefore, my PhD project focused on deciphering the complex protein-protein interactions of MOB1 with MST1/2, LATS1/2 and NDR1/2. To do so, we generated a series of MOB1 variants that are selectively impaired in their binding to NDR1/2 (Trc), MST1/2 (Hippo), or LATS1/2 (Warts) in human (fly) cells. Using these selective lossof-interaction (SLOI) variants we studied the effects of MOB1 overexpression on the proliferation and anchorage-independent growth of human cancer cell lines, thereby establishing which MOB1 interactions are required for the tumour suppressive role of MOB1. Equally importantly, we found that human MOB1 can restore the survival of mats loss-of-function (LOF) in Drosophila. By generating and studying transgenic flies expressing our SLOI MOB1 variants combined with Mats LOF, we discovered that the Hippo/MOB1A interaction is dispensable for fly development and reproduction, while the Trc/MOB1A and Wts/MOB1A interactions are essential. Taken together, my PhD thesis defined a completely novel panel of MOB1 SLOI variants to study the importance of MOB1 interactions. By studying transgenic human cells lines and flies expressing these SLOI variants we delineated which MOB1 interactions are essential for life of a complex multicellular organisms and for tumour suppression in human cancer cells. Collectively, our findings suggest that the Hippo/MOB1 interaction is neither required for life nor for tumour suppression, while the other interactions of MOB1 with Hippo core cassette kinases are essential in a context-dependent manner.

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