University of California, San Francisco
533 Parnassus Avenue, Room S-1032
San Francisco, CA. 94143-0795
p: 415-476-1291
f: 415-502-5081
e: aweiss@medicine.ucsf.edu
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. He is currently the Ephraim P. Engleman Distinguished Professor of Rheumatology and an Investigator of the Howard Hughes Medical Institute. 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 lymphocyte 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 activate 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 PTKs 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. Recent studies suggest that CD148 has unique and overlapping functions with CD45 in B cells, 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
Au-Yeung, B.B., Deindl, S., Hsu, L.Y., Palacios, E.H., Levin, S.E., Kuriyan, J., and Weiss, A. The structure, regulation and function of Zap-70. Immunol. Rev., 228:41-57, 2009.
Das, J., Ho, M., Zikherman, J., Govern, C., Yang, M., Weiss, A., Chakraborty, A.K., and Roose, J.P. Digital signaling and hysteresis characterize Ras activation in lymphoid cells. Cell, 136:337-351. 2009.
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.
Hsu, L.-Y., Tan, Y.X., Xiao, Z., Malissen, M., and Weiss, A. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J. Exp. Med., 206:2527-2541, 2009
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., 283:15419-15430. 2008.
Hermiston, M.L., Zikherman, J., Tan, A.L., Lam, V., Cresalia, N.M., Oksenberg, N., Goren, N., Brassat, D., Oksenberg, J.R., and Weiss, A. Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses. Proc. Natl. Acad. Sci. USA, 106:546-551. 2009.
Phee, H., Dzhagalov, I., Mollenauer, M., Wang, Y., Irvine, D.J., Robey, E., and Weiss, A. Regulation of thymocyte positive selection and motility by GIT2. Nat. Immunol., 11:503-511. 2010.
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.
Zikherman, J., Hermiston, M., Steiner, D., Hasegawa, K., Chan, A. and Weiss, A. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J. Immunol., 182:4093-4106. 2009.
Zikherman, J., Jenne, C., Watson, S., Doan, K., Raschke, W., Goodnow, C.C., and Weiss, A. The balance between positive and negative regulatory roles of CD45 during TCR signaling varies throughout T cell development. Immunity, 32:342-354. 2010.
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