Characterization of 72 and 52 kDa inositol polyphosphate 5-phosphatases: role in vesicular trafficking and cell death

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Cells respond to the external environment, stress, hormones and grow th factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes or kinases that modify these membrane lipids in particular an enzyme known as the PI 3-kinase generate potent signalling molecules that regulate cell growth. It has been shown by many studies that signals generated by the PI 3-kinase are amplified in certain human cancers. Inherited cancer syndromes have been described in which the cell has lost the ability to switch off these lipid messenger molecules. The current project aims to investigate two recently identified enzymes called 5-phosphases that have the ability to terminate PI 3-kinase membrane signals. Both these enzymes were isolated and characterized by the host laboratory and it is predicted they will play distinct roles in the cell. The 72 kDa 5-phosphatase is predicted to regulate protein and vesicular trafficking to the surface of cell. This proposal aims to investigate if the 72 kDa 5-phosphatase can regulate the intracellular sorting of new proteins within the cell. We have also noted the 72 kDa 5-phosphatase may play a role in the development of the nervous system in particular the ability of nerves to send branches out and differentiate. This proposal will investigate this hypothesis. The second enzyme that we have isolated is a 52 kDa 5-phosphatase. This enzyme is present in many cells. We have compelling evidence that the enzyme forms a complex with a recently decribed protein called SODD that stops cells from dying in response to inappropropirate signals. We predict the 52 kDa 5-phosphatase may function to prevent prolonged cell survival as is observed in cancer. We will investigate if this enzyme regulates the cell death pathway and if increased or decreased levels of the 52 kDa 5-phosphatase alter cell survival