PI3K-III COMPLEX · The PI3K-III complex: Function in cell regulation and tumour suppression

Phosphoinositides (PIs), phosphorylated derivatives of phosphatidylinositol (PtdIns), control cellular functions through recruitment of cytosolic proteins to specific membranes. Among the kinases involved in PI generation, the PI3K-III complex, which catalyzes conversion of PtdIns into PtdIns 3-phosphate (PI3P), is of great interest for several reasons. Firstly, it is required for three topologically related membrane involution processes - the biogenesis of multivesicular endosomes, autophagy, and cytokinesis. Secondly, through its catalytic product this protein complex mediates anti-apoptotic and antiproliferative signalling. Thirdly, several subunits of the PI3K-III complex are known tumour suppressors, making the PI3K-III complex a possible target for cancer therapy and diagnostics. This proposal aims to undertake a systematic analysis of the PI3K-III complex and its functions, and the following key questions will be addressed: How is the PI3K-III complex recruited to specific membranes? How does it control membrane involution and signal transduction? By which mechanisms do subunits of this protein complex serve as tumour suppressors? The project will be divided into seven subprojects, which include (1) characterization of the PI3K-III complex, (2) detection of the PI3K-III product PI3P in cells and tissues, (3) the function of the PI3K-III complex in downregulation of growth factor receptors, (4) the function of the PI3K-III complex in autophagy, (5) the function of the PI3K-III complex in cytokinesis, (6) the function of the PI3K-III complex in cell signalling, and (7) dissecting the tumour suppressor activities of the PI3K-III complex. The analyses will range from protein biochemistry to development of novel imaging probes, siRNA screens for novel PI3P effectors, functional characterization of PI3K-III subunits and PI3P effectors in cell culture models, and tumour suppressor analyses in novel Drosophila models.