The growth, differentiation, and effector functions of many tissues are regulated by cell surface receptors that transduce signals via the activation of protein tyrosine kinases. It has become clear only in the past three years that a parallel receptor set exists which functions to attenuate or deviate responses transduced by many of these activating receptors. As a general rule, these receptors must associate physically or be coaggregated with their counterparts in order to function and utilize phosphatases as effectors. The best studied examples of these receptors, FcgammaRIIB1, KIR, and CTLA4, are found in the immune system where they function to modulate various immunologic functions. Functional deficiency in the receptors or their effectors appears to lead to autoimmunity and, in the case of CTLA4, to life-threatening lymphadenopathy. Hyperactivity presumably leads to immunodeficiency. This proposal is focused on defining the molecular mode of action of a prototypic member of this family, FcgammaRIIB1. FcgammaRIIB1 is a receptor for IgG constant regions that functions to modify signals transduced through coaggregated antigen receptors, most notably the B cell antigen receptor. It is hypothesized that the FcgammaRIIB1 cytoplasmic tail contains distinctly compartmentalized structural information for the activation of multiple distinct biochemical pathways that impinge on antigen receptor signaling. The proposed studies will utilize genetic, biochemical, and biologic approaches in an effort to achieve the long term goals of elucidating these pathways and their targets.
Specific aims of this proposal are to: 1) identify previously unrecognized receptor tyrosil phosphorylation sites and define their effectors; 2 and 3) undertake mutational analysis to define the sites within the receptor that function in transduction of specific inhibitory signals; and 4) define the role of the adaptor p62Dok in FcgammaRIIB1 signaling. The proposed studies will advance our understanding of signal transduction by this family of regulatory receptors and may reveal new and attractive targets for therapeutic intervention in cancer, inflammation, autoimmunity and immunodeficiency.
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