Zhu, M, Zou, J, Li, T, O'Brien, SA, Zhang, Y, Ogden, S, and Zhang, W. "Differential Roles of Phospholipase D Proteins in FcεRI-Mediated Signaling and Mast Cell Function." Journal of immunology (Baltimore, Md. : 1950) 195, no. 9 (November 2015): 4492-4502.
Weiguo Zhang, PhD
Activation via the T-cell antigen receptor (TCR) triggers a cascade of intracellular biochemical events eventually leading to T-cell proliferation and effector functions. One of the earliest events is the activation of the Src family tyrosine kinases Fyn and Lck. The activated Src family kinases phosphorylate the CD3 subunits and TCRζ chains. ZAP-70 tyrosine kinase is recruited to the antigen receptors via the binding to CD3 and TCRζ. ZAP-70 is then tyrosine phosphorylated by these Src family kinases and thus activated. These activated tyrosine kinases further phosphorylate a number of intracellular proteins, such as PLC-γ1, Vav, Cbl, SLP-76, and LAT, and activate downstream signaling pathways including the Ras-MAPK pathway and Ca2+flux. Activation of these two pathways is required for AP-1 and NFAT-mediated transcription, IL-2 production, and T-cell proliferation.
Our primary interest of the laboratory is to understand the role of membrane-associated adaptor proteins in lymphocyte activation, development, and immune response. One of these proteins is LAT (Linker for Activation of T-cells). LAT is tyrosine phosphorylated upon T-cell activation and associates with several signaling molecules including Grb2, Gads, and PLC-γ1. LAT-deficient T-cells are defective in the Ras-MAPK activation and Ca2+ flux after the TCR engagement. LAT knockout mice have an early block in thymocyte development. Interestingly, mice with a mutation in LAT develop a severe autoimmune disease. We are investigating how LAT interacts with other signaling proteins and how LAT regulates T cell activation and immune responses.
In addition to LAT, we are working on two LAT-like molecules, LAB and LAX. We have generated mice deficient in these proteins and are analyzing the phenotypes of these mice to determine the role of these proteins in lymphocyte signaling and immune responses.
We are also interested in FcεRI-mediated signaling. We are working on the role of LAT, LAB, and RasGRP1 in FcεRI-mediated signaling, mast cell function, and allergic responses.
Our long-term goal is to understand the details of immunoreceptor-mediated signaling pathways. Understanding these signaling pathways may identify therapeutic targets that could facilitate the development of drugs that suppress, modify, or augment immune responses in autoimmunity, transplantation, allergy, and cancer.
Education and Training
- Postdoctoral Fellow, Cell Biology And Metabolism Branch, National Institutes of Health, 1995 - 1999
- Postdoctoral Fellow, Microbiology And Immunology, Yeshiva University New York, 1994 - 1995
- Ph.D., Yeshiva University New York, 1994
Selected Grants and Awards
- Organization and Function of Cellular Structure
- Basic Immunology Training Program
- Training Program in Inflammatory and Immunological Diseases
- Phospholipase D proteins in immunoreceptor-mediated signaling
- Analysis of adaptor protein (LAT) in TCR signaling
- Regulation of thymocyte maturation and mature T lymphocyte homeostasis by c-FLIP
- Adaptor molecules in lymphocyte signaling
- A novel pathway regulating cytokine production and asthma development
- Development And Persistence Of Immunity In SCID Chimeras
O'Brien, SA, Zhu, M, and Zhang, W. "The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity." Journal of immunology (Baltimore, Md. : 1950) 195, no. 2 (July 2015): 695-705.
Sullivan, SA, Zhu, M, Bao, S, Lewis, CA, Ou-Yang, C-W, and Zhang, W. "The role of LAT-PLCγ1 interaction in γδ T cell development and homeostasis." Journal of immunology (Baltimore, Md. : 1950) 192, no. 6 (March 2014): 2865-2874.
Suzuki, R, Leach, S, Liu, W, Ralston, E, Scheffel, J, Zhang, W, Lowell, CA, and Rivera, J. "Molecular editing of cellular responses by the high-affinity receptor for IgE." Science (New York, N.Y.) 343, no. 6174 (February 6, 2014): 1021-1025.
Ou-Yang, C-W, Zhu, M, Sullivan, SA, Fuller, DM, and Zhang, W. "The requirement of linker for activation of T cells in the primary and memory responses of CD8 T cells." J Immunol 190, no. 6 (March 15, 2013): 2938-2947.
Ou-Yang, C-W, Zhu, M, Fuller, DM, Sullivan, SA, Chuck, MI, Ogden, S, Li, Q-J, and Zhang, W. "Role of LAT in the granule-mediated cytotoxicity of CD8 T cells." Mol Cell Biol 32, no. 14 (July 2012): 2674-2684.
Zhu, M, Fuller, DM, Ou-Yang, C-W, Sullivan, SA, and Zhang, W. "Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB." J Immunol 188, no. 6 (March 15, 2012): 2733-2741.
Zhu, M, Fuller, DM, and Zhang, W. "The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development." J Biol Chem 287, no. 11 (March 9, 2012): 8135-8143.
Shen, S, Chuck, MI, Zhu, M, Fuller, DM, Yang, C-WO, and Zhang, W. "The importance of LAT in the activation, homeostasis, and regulatory function of T cells." J Biol Chem 285, no. 46 (November 12, 2010): 35393-35405.
Chuck, MI, Zhu, M, Shen, S, and Zhang, W. "The role of the LAT-PLC-gamma1 interaction in T regulatory cell function." J Immunol 184, no. 5 (March 1, 2010): 2476-2486.
Shen, S, Lau, J, Zhu, M, Zou, J, Fuller, D, Li, Q-J, and Zhang, W. "The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-alpha motif domain in thymic selection and T-cell activation." Blood 114, no. 1 (July 2, 2009): 74-84.
Shen, S, Zhu, M, Lau, J, Chuck, M, and Zhang, W. "The essential role of LAT in thymocyte development during transition from the double-positive to single-positive stage." J Immunol 182, no. 9 (May 1, 2009): 5596-5604.
Zhu, M, Koonpaew, S, Liu, Y, Shen, S, Denning, T, Dzhagalov, I, Rhee, I, and Zhang, W. "Negative regulation of T cell activation and autoimmunity by the transmembrane adaptor protein LAB." Immunity 25, no. 5 (November 2006): 757-768.
Zhu, M, Rhee, I, Liu, Y, and Zhang, W. "Negative regulation of Fc epsilonRI-mediated signaling and mast cell function by the adaptor protein LAX." J Biol Chem 281, no. 27 (July 7, 2006): 18408-18413.
Koonpaew, S, Shen, S, Flowers, L, and Zhang, W. "LAT-mediated signaling in CD4+CD25+ regulatory T cell development." J Exp Med 203, no. 1 (January 23, 2006): 119-129.