Cell division control in the changing environment

Abstract

Cell growth and cell cycle progression are tightly controlled in order to provide optimal proliferation in a particular environment. The activities of multiple signalling pathways are a prerequisite for the progression through the cell cycle and for the increase in cell number. These activities need to be constantly monitored and adjusted to the particular conditions such as nutrient availability or exposure to stress. Failure to properly regulate key signalling pathways could be fatal leading to cell death. This study aims to enhance our understanding of how endogenous inhibitors of the two main signalling pathways, the stress MAP kinase and TOR pathways, are controlled and how these controls are translated into target/substrate activity. The first part of the study is dedicated to analysis of Pyp2, a Sty1 MAPK phosphatase. Pyp2 and Pyp1 are both tyrosine specific phosphatases and are responsible for Sty1 inactivation. Despite the high degree of similarity between these molecules, in particular conditions cells depend only on proper Pyp2 and not Pyp1 regulation. A combination of biological and biochemical tools with additional help from bioinformatics allowed the identification of a key regulatory "domain" present only in Pyp2, the linker region. This region is subjected to Sty1-dependent phosphorylation, which in turn increases Pyp2 stability. Detailed linker region analysis suggests that Sty1 has the possibility to auto-regulate through control of Pyp2 protein stability. The second part of this study aims to characterise what appears to be a novel inhibitor of TOR signalling. Two independent screens set to find new regulators of TOR signalling identified the Ppk32 kinase as a potential new regulator in the TOR pathway. A further characterisation indicates that Ppk32 can significantly reduce TOR activity and eventually block cell growth. Altered traffic through the endomembrane systems in the absence of Ppk32 suggests that this molecule may directly or indirectly alter TOR signalling via an effect on internal membranes.

Date of Award	1 Aug 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stephen Taylor (Supervisor) & Janni Petersen (Supervisor)