The Bimps (BcI10 Interacting MAGUK Proteins) are a newly described family of signaling proteins that activate the pro-survival transcription factor, NF-kappaB. Bimps belong to the larger MAGUK (Membrane Associated Guanylate Kinase) family, a class of proteins composed of multiple distinct protein/protein interaction domains that function as molecular scaffolds in assembling multiprotein complexes at the plasma membrane. Bimps bind to and operate upstream of Bcl10, an NF-kappaB signaling molecule that is known to be an essential mediator of lymphocyte proliferation in response to antigen. The genes encoding Bcl10 and its downstream binding partner, MALT1, are each targets of recurrent chromosomal translocation in mucosa associated lymphoid tissue (MALT) lymphoma, suggesting that perturbation of the Bcl10-mediated NF-kappaB signaling pathway can promote lymphomatous transformation. Our preliminary data suggest that the Bimp proteins function to link surface receptor signaling and subsequent protein kinase C (PKC) activation to Bcl10-mediated induction of NF-(B. We hypothesize that the lymphocyte specific Bimp isoform, Bimp3, functions as a scaffold to assemble the signaling molecules that are required for Bcl10/MALT1-mediated NF-(B activation in response to lymphocyte antigen receptor stimulation. Furthermore, we hypothesize that disruption of the normal mechanisms by which the antigen receptor and Bimp3 regulate Bcl10 and MALT1 activity, as a consequence of chromosomal translocation, contributes to the pathogenesis of MALT lymphoma. In order to test these hypotheses, we propose three specific aims: 1) Determine if Bimp3, Bcl10 and MALT1 participate in a common NF-(B signaling pathway in lymphocytes with known antigen receptor-related signaling molecules; 2) Delineate the function of the individual protein/protein interaction domains within the Bimp3 structure, and 3) Characterize the physiological role of Bimp3 by generating and analyzing mice deficient in Bimp3. The career development program outlined in this proposal will build upon the investigator's prior research experience and will also provide the opportunity to master new laboratory techniques, to interact with a new mentor and team of collaborators, and to participate in additional didactic training in immunology, mouse genetics and bioinformatics. This training experience will ultimately lead to transition to the status of independent investigator.
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