? To analyze the rules governing the subunit assembly of PP2A.
? To follo w the subunit composition during cell cycle, cell growth and cellular localisati on. New tools will be developed.
? To analyse the role of PP2A in controlli ng signal transduction events in the G1 phase of the cell cycle leading to the S phase: interaction of PP2A with cdc25A, cdc25B, PKC, PKB, raf and viral mT and sT.
? To analyse the role of PP2A in controlling check point-dependent process es in the G2-M phase of the cell cycle: interaction of PP2A with the dynamic mic rotubuli and cdc25
Reversible protein phosphorylation plays a critical role in signal transduction events controlling cell division, cell growth, differentiation and malignant transformation. Since malfunction of the key regulator protein phosophatase 2A (PP2A) is suspected to be the underlying cause of tumour formation in several situations, this project will concentrate on the role ofPP2A in the regulation of cell division and proliferation. Specifically we will address the nature of the different forms of PP2A by examining the subunit composition during cell cycle in mammalian cells and in different tumour cells. In addition to identifying which partners associate with the PP2A catalytic subunit during cell growth, we will investigate if the changes in subunit composition can be correlated with specific post-translational modifications of PP2A (in particular methylation and phosphorylation). Further studies will examine how association with different partner proteins alters the in vitro activity of PP2A.These studies will be coupled to and developed within an analysis of the regulation by PP2A of master players in cell division. This work will include: cdc25, cyclin dependent kinases, mitotic assembly/disassembly of microtubules, several of the protein kinases involved in distinct mitogen stimulated signal transduction pathways (e.g. PKB, PKC, Raf) and finally the subversion of PP2A function by DNA tumour viruses. 02 02
Funding SchemeCSC - Cost-sharing contracts
WC2A 3PX London
W12 0NN London