Coruche Gaspar, PM; (2013) Investigating the Role of the Actin Cytoskeleton in Hippo Signalling. Doctoral thesis , UCL (University College London).

Abstract

The Hippo pathway is composed of a phosphorylation cascade involving the kinases Hippo/MST and Warts/LATS, which inactivate the pro-growth transcriptional co-activator Yorkie/YAP. By sensing the status of the actin cytoskeleton, Yorkie/YAP is believed to respond to cell crowding and the rigidity of the environment, but the molecular details and in vivo relevance of this remain unclear. I have investigated the role of mechanical cues and the actin cytoskeleton, in the regulation of Yorkie/YAP. I have applied several forms of mechanical stresses to cell cultures and present evidence to suggest that cell-substrate adhesion and compliance plays role in regulating the localization of YAP. The transduction of mechanical signals is often mediated by the force-displacement of cytoskeletal elements within the cell. Therefore, I took a genetic approach to analyse the contribution of the actin cytoskeleton to Yorkie regulation in Drosophila. Surprisingly, I showed that the Hippo pathway restricts apical F-actin levels in some epihtelia. My work also revealed a novel function of actin-polymerization-factors, such as Capping Proteins, Zyxin and Enabled in regulating Yorkie activity. I have recovered the genes zyxin and ajuba in a modifier screen for actin-associated molecules that modulate hippo-dependent growth. I established that Zyxin is a positive regulator of Yorkie activity, being sufficient to drive epithelial growth and activation of the Yorkie target gene expanded. Interestingly, Expanded was shown to bind Yki directly and is believed to act as a Yki cytoplasmic tether. I have shown that Zyxin can interact with Expanded and prevent its association with Yki, leading me to hypothesize that Zyxin might antagonise Expanded function. Finally, I show that Drosophila Zyxin interacts with the actin-polymerisation-factor Enabled and this is essential to promote tissue growth and Yorkie activity. Furthermore, I establish that Capping Proteins can antagonize the function of Zyxin to restrict tissue growth.

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