CD45 REGULATION OF ANTIGEN RECEPTOR SIGNALING

DESCRIPTION: a. Candidate: Dr. Erik Peterson received his M.D. degree from the University of Minnesota in 1990. He then trained in internal medicine at the University of Colorado, Denver. He is currently a rheumatology fellow at the University of Iowa College of Medicine. Dr. Peterson joined his sponsor's laboratory in July 1995. b. Sponsor: Dr. Gary Koretzky is Associate Professor of Medicine and Rheumatology in the Departments of Internal Medicine and Physiology and Biophysics at the University of Iowa College of Medicine. c. Environment: The research will be carried out in the sponsor's laboratory at the University of Iowa. d. Training Plan: (Adapted from the Abstract) This request for a Mentored Clinical Scientist Development Award presents a program of directed study in immunology and molecular biology combined with a research project. Course work and supervised bench research work will take place during Phase I of the project. Phase II will increasingly focus on the research project and is coupled with expanded independence and responsibility of the principal investigator. The objective of the research project is to define the regions of CD45 that are required for B and T cell signaling and substrate binding and to define the regions of LPAP that are important for binding CD45 to its substrates and for causing LPAP instability in CD45-deficient cells. CD45, a transmembrane protein tyrosine phosphatase, is required for effective T cell antigen receptor signaling in lymphocytes. Early evidence from CD45-deficient B cell lines supports a critical role for CD45 in B cell receptor signaling as well. Two molecules uniformly associate with CD45 in T cells: the src family kinase lck and lymphocyte phosphatase associated phosphoprotein (LPAP). One model of how CD45 acts to regulate lymphocyte signaling proposes that CD45 dephosphorylates and activates lck. A corollary model proposes that LPAP acts to enhance the association between CD45 and its substrates, thereby increasing signaling efficiency. The proposed research will test aspects of these models of CD45 and LPAP function in leukemic cell lines. Mutagenized cDNA will be transfected into these cells to examine the function of various sequences of these molecules. The research project also aims to determine if LPAP homologues exist in other tissues.