ANNEXIN PHOSPHORYLATION: CAUSES AND CONSEQUENCES

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DESCRIPTION (Applicant's abstract): The annexins are calcium-dependent, phospholipid-binding proteins that are the major peripheral proteins that move on and off membranes in response to calcium signalling events in cells. Evidence suggests they regulate a number of enzyme activities on membranes such as protein kinases and phospholipases, they act as receptors and docking sites for other proteins on the membrane, and they may mediate membrane-membrane interactions underlying exocytosis, endocytosis, and organelle tra.fficking. A number of annexins are phosphorylated in response to cell stimulation by secretogogues, growth factors, and oncogenic kinases. This project seeks to understand the most important ftinctions of annexins by identifying the physiological and pathological conditions under which they are phosphorylated, the protein kinases involved, and the consequences of the phosphorylation in terms of the regulation of cellular activities. The structure of annexin VI with a mutation that mimics phosphorylation will be determined by X-ray crystallography. The conformation of native and mutant annexin VI on lipid monolayers will be determined by electron microscopy of 2 dimensional crystals. Proteins that dock onto the phosphorylation sites on annexins will be characterized. The influence of phosphorylation on the locations and movements of annexins in cells will be determined, including the movements of annexins into the nucleus of the cell. These fundamental studies on the organization of membranes and their associated proteins should lead to a better understanding of cell signalling events that underlie the release of hormones and neurotransmitters and the regulation of cell growth under normal and pathological conditions.