GENETIC ANALYSIS OF REGULATION AND FUNCTION OF CD45

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The leukocyte common antigen CD45 has received considerable attention recently as evidence accumulates for its role in signal transduction during immune responses. CD45 has the interesting properties of (a) expression restricted to nucleated hematopoietic cells, (b) multiple isoforms which differ in the extracellular domain, (c) strictly regulated expression of the different isoforms in the various hematopoietic lineages, (d) a large cytoplasmic domain with protein tyrosine phosphatase (PTPase) activity and (e) associations with complexes at the cell surface involved in signal transduction. The CD45 molecule appears to be an important participant in the function of the cells expressing it. Studies with cell lines have indicated CD45 is essential for optimal signaling via cell surface receptors on T and B lymphocytes and possibly, by extrapolation, other hematopoietic lineage cells. The PTPase activity of the cytoplasmic domain appears critical for the signaling function. The model that is emerging is CD45 functions to control the state of phosphorylation of src family protein tyrosine kinases, members of which have been shown to play roles in signaling through the T cell receptor and B cell antigen receptor. The principal studies to date that have led to our present concept of CD45 function have used artificial in vitro systems. A major issue hindering progress in answering further questions concerning CD45 and its role is the poor ability to express CD45 from its cDNA. Even when successful, other promoters not having the distinctive expression characteristics of CD45 have had to be used. The experiments proposed address the function of CD45 structural components in vivo by introducing mutations into the complete CD45 gene. The roles of the extracellular domain, the cytoplasmic domain and critical functional sites will be evaluated in this manner.