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p:
415-476-1291
f: 415-502-5081
e: aweiss@medicine.ucsf.edu
University
of California, San Francisco
533 Parnassus Avenue, Room S-1032
San Francisco, CA. 94143-0795
Dr. Weiss received his Ph.D. (Immunology, 1978) and M.D. (1979) degrees from the University of Chicago. He did a postdoctoral fellowship at the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland. Dr. Weiss completed his training in internal medicine and rheumatology at UCSF. In 1985, he joined the faculty of the Division of Rheumatology and the Howard Hughes Medical Institute at the University of California, San Francisco. His major academic activities include directing his research laboratory as well as serving as Chief of the Division of Rheumatology. Dr. Weiss is a member of the National Academy of Sciences, Institute of Medicine and the American Academy of Arts and Sciences.
Research
Interests
Many rheumatologic diseases result from the abnormal activity of the immune system. In order to understand the mechanisms responsible for the abnormal activity of lymphocytes of the immune system, the normal mechanisms responsible for regulating their functions must be understood. The Weiss lab is interested in the biochemical signal transduction mechanisms that control T and B cell responses. The response to antigen by lymphocytes involves complex molecular interactions involving multiple cell surface receptors.
Following the recognition of foreign antigens or auto-antigens, antigen receptors on lymphocytes interact with members of the Src, Syk and Tec families of cytoplasmic protein tyrosine kinases (PTKs), enzymes that mediate protein phosphorylation. By initiating protein phosphorylation, these enzymes are responsible for regulating downstream signaling pathways that lead to cellular responses. Studies are ongoing to understand how expression of antigen receptors are regulated and how they activates cytoplasmic PTKs. Furthermore, understanding the signaling pathways downstream of these PTKs will be critical for our understanding of the normal and abnormal state of the immune system.
The action of protein kinases is opposed by that of protein phosphatases. The Weiss lab has focused on the functions of two receptor-like protein tyrosine phosphatases (RPTPs), CD45 and CD148. CD45 is a very abundant RPTP that is expressed on hematopoietic cells. It regulates antigen receptor signal transduction by influencing the activity of Src PTKs. Dimerization of CD45 negatively regulates its function. This contrasts with the activating effects of ligands for most receptors. Inactivation of this inhibitory mechanism for CD45 leads to lymphoproliferation and autoimmunity, resembling lupus. Current studies are focused on regulation of CD45 dimerization and the effects of disrupting the dimerization-mediated inhibitory mechanism. These studies highlight the importance of precisely regulating tyrosine phosphorylation signaling pathways in lymphocytes. Recent studies suggest that CD148 has unique and overlapping functions with CD45 in B cell, macrophages and platelets.
Studies in the Weiss lab seek to understand the biochemical signaling pathways that normally regulate the immune responses of lymphocytes to pathogens. These very same signaling events are involved in pathologic activation of the immune system, as occurs in rheumatoid arthritis and lupus. The goal is to understand the mechanisms that turn the protective immune system into one that can cause harm.
Recent Publications
Deindl, S., Kadlecek, T.A. , Brdicka, T., Cao, X., Weiss, A., and Kuriyan, J. Structural basis for the inhibition of the tyrosine kinase activity of ZAP-70. Cell, 129:735-746, 2007.
Hermiston, M., Tan, A.L., Gupta, V.A., Majeti, R., and Weiss, A. The juxtamembrane wedge negatively, regulates CD45 function in B cells. Immunity, 23:635-647, 2005.
Levin, S.E., Zhang, C., Kadlecek, T.A., Shokat, K. and Weiss, A. Inhibition of ZAP-70 kinase activity via an analog-sensitive allele blocks T cell receptor and CD28 superagonist signaling. J. Biol. Chem. in press, 2008.
Myers, M.D., Sosinowski, T., Dragone, L.L., White, C., Band, H., Gu, H., and Weiss, A. Src-like adaptor protein regulates TCR expression on thymocytes by adapting c-Cbl to the TCR complex. Nature Immunol. 7:57-66, 2006.
Rassenti, L.Z., Huynh, L., Toy, T.L., Chen, L., Gribben, J.G., Keating, M.J., Rai, K.R., Finn, I.W., Byrd, J.C., Kay, N.E., Greaves, A., Weiss, A., Kipps, T.J. ZAP-70 compared with immunoglobulin heavy-chain mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N. Eng. J. Med., 351:893-901. 2004.
Zhu, J.W.*, Brdicka, T.*, Katsumoto, T.R., Lin, J. and Weiss, A. Structurally distinct phosphatases CD45 and CD148 regulate B cell and macrophage immunoreceptor signaling. Immunity, 28:183-196. 2008.
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