Regulation of the hematopoietic-cell transmembrane phosphatases CD45 and CD148

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DESCRIPTION (provided by applicant): CD45 and CD148 are transmembrane tyrosine phosphatases that regulate antigen-receptor signaling and thus strongly influence the sensitivity of the mammalian immune response. They potentiate signal transduction by dephosphorylating the C-terminal tail of the Src-family kinases, which releases autoinhibitory interactions and allows kinase activation. High levels of these phosphatases, however, attenuate signaling. The molecular mechanisms by which CD45 and CD148 are regulated are unclear. There is evidence that CD45 is inhibited by dimerization, but some studies suggest that an inactive pseudophosphatase domain, present in CD45 but not in CD148, may interfere with dimer formation. Using the purified cytoplasmic domains of CD45 and CD148 localized to artificial membranes, I will examine whether dimerization inhibits phosphatase activity. I will investigate how the pseudophosphatase domain contributes to CD45 function by testing whether it blocks dimerization, tethers substrates, or serves as an allosteric modulator upon phosphorylation. Finally, I will examine the possibility that there are direct interactions between CD45 and CD148 in cells by determining whether they heterodimerize on the cell surface. Understanding the regulatory mechanisms of the phosphatases that control the activation and proliferation of hematopoietic cells will be important for understanding the sensitivity and control mechanisms of the immune response. Public Health Relevance: The tyrosine phosphatase proteins CD45 and CD148 are found at high levels in the cells of the immune system and are important for controlling the sensitivity of the immune response. Mutations in CD45 have been proposed to be associated with several autoimmune diseases in humans and mice, including lupus, Graves disease, autoimmune lymphoproliferation, and multiple sclerosis. CD148 suppresses cell growth and cancer in several cell types, but its function in the cells of the immune system is not yet clear. Understanding the regulation of these signaling proteins will help us better understand the balance of signals necessary for maintaining appropriate growth patterns and sensitivity in immune cells