Biological definition of Fc receptor homologs

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DESCRIPTION (provided by applicant): This proposal describes a five-year training program for development of an academic career in Hematology. The candidate, a postdoctoral fellow in Hematology/Oncology, is board certified in Internal Medicine. Research training in Immunology under the supervision of Dr. Max Cooper is proposed for the first two to three years to expand the candidate's scientific knowledge in lymphocyte and receptor biology in order to achieve research independence. The research project focuses on characterization of one of the members of a multi-gene family of Ig-like receptors expressed by B lymphocytes that were co-discovered by the candidate on the basis of their homology with classical immunoglobulin Fc receptors. The putative receptors encoded by most of these genes, provisionally named Fc receptor homologs (FcRH1-5), have Ig-like domain sequences that suggest Fc binding capacity and cytoplasmic domains with tyrosine-based sequences possessing consensus activating or inhibitory motifs. FcRH1-5 are differentially expressed during B cell differentiation in peripheral lymphoid tissues and in different types of B lineage malignancies. FcRH3, the family member that is the focus of this proposal, is predicted to encode a type-I glycoprotein with six Ig-like domains, an uncharged transmembrane segment, and a cytoplasmic domain containing both activation and inhibitory tyrosine-based consensus motifs. Comparative Ig-domain analysis of FcR and FcRH family members suggests that FcRH3 may have Fc binding capacity, and pilot studies support this possibility. For use in determining which cells express FcRH3 and its biochemical nature, monoclonal antibodies will be produced against recombinant FcRH3 protein. In order to confirm the Fc receptor capacity of FcRH3, Ig-binding assays will be performed utilizing purified human myeloma Igs of different isotypes and their Fc fragments. Native FcRH3 expressing cells will be used to search for associated molecules in immunoprecipitation analyses. The anti-FcRH3 antibodies and the native ligands will be used in receptor ligation studies to examine the signaling capacity of the cytoplasmic tyrosine-based consensus motifs. The studies proposed here focus on expression and function of one family member, and serve as a prototypic model for future characterization of the other seven Fc receptor homolog family members and their roles in normal and pathologic conditions.