Weiguo Zhang

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Associate Professor of Immunology
Department:
Immunology
Address:
112 Jones Builidng, 207 Resear
Box 3010 DUMC
Durham, NC 27710
Office Telephone:
(919) 613-7803
Research Interests:

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.
Representative Publications:
  • Fuller, DM; Zhu, M; Koonpaew, S; Nelson, MI; Zhang, W. The importance of the Erk pathway in the development of linker for activation of T cells-mediated autoimmunity. Journal of Immunology. 2012;189:4005-4013.  Abstract
  • Ou-Yang, CW; Zhu, M; Fuller, DM; Sullivan, SA; Chuck, MI; Ogden, S; Li, QJ; Zhang, W. Role of LAT in the granule-mediated cytotoxicity of CD8 T cells. Molecular and Cellular Biology. 2012;32:2674-2684.  Abstract
  • Zhu, M; Fuller, DM; Ou-Yang, CW; Sullivan, SA; Zhang, W. Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB. Journal of Immunology. 2012;188:2733-2741.  Abstract
  • Zhu, M; Fuller, DM; Zhang, W. The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development. Journal of Biological Chemistry. 2012;287:8135-8143.  Abstract
  • Chuck, MI; Zhu, M; Shen, S; Zhang, W. The role of the LAT-PLC-gamma1 interaction in T regulatory cell function. Journal of Immunology. 2010;184:2476-2486.  Abstract
  • Shen, S; Chuck, MI; Zhu, M; Fuller, DM; Yang, CW; Zhang, W. The importance of LAT in the activation, homeostasis, and regulatory function of T cells. Journal of Biological Chemistry. 2010;285:35393-35405.  Abstract
  • Shen, S; Lau, J; Zhu, M; Zou, J; Fuller, D; Li, QJ; 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. 2009;114:74-84.  Abstract
  • Shen, S; Zhu, M; Lau, J; Chuck, M; Zhang, W. The essential role of LAT in thymocyte development during transition from the double-positive to single-positive stage. Journal of Immunology. 2009;182:5596-5604.  Abstract
  • Koonpaew, S; Shen, S; Flowers, L; Zhang, W. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. Journal of Experimental Medicine. 2006;203:119-129.  Abstract
  • Zhu, M; Koonpaew, S; Liu, Y; Shen, S; Denning, T; Dzhagalov, I; Rhee, I; Zhang, W. Negative regulation of T cell activation and autoimmunity by the transmembrane adaptor protein LAB. Immunity. 2006;25:757-768.  Abstract
  • Zhu, M; Rhee, I; Liu, Y; Zhang, W. Negative regulation of Fc epsilonRI-mediated signaling and mast cell function by the adaptor protein LAX. Journal of Biological Chemistry. 2006;281:18408-18413.  Abstract
  • Zhu, M; Granillo, O; Wen, R; Yang, K; Dai, X; Wang, D; Zhang, W. Negative regulation of lymphocyte activation by the adaptor protein LAX. Journal of Immunology. 2005;174:5612-5619.  Abstract
  • Zhu, M; Shen, S; Liu, Y; Granillo, O; Zhang, W. Cutting Edge: Localization of linker for activation of T cells to lipid rafts is not essential in T cell activation and development. Journal of Immunology. 2005;174:31-35.  Abstract
  • Janssen, E; Zhu, M; Craven, B; Zhang, W. Linker for activation of B cells: a functional equivalent of a mutant linker for activation of T cells deficient in phospholipase C-gamma1 binding. Journal of Immunology. 2004;172:6810-6819.  Abstract
  • Koonpaew, S; Janssen, E; Zhu, M; Zhang, W. The importance of three membrane-distal tyrosines in the adaptor protein NTAL/LAB. Journal of Biological Chemistry. 2004;279:11229-11235.  Abstract
  • Zhu, M; Liu, Y; Koonpaew, S; Granillo, O; Zhang, W. Positive and negative regulation of FcepsilonRI-mediated signaling by the adaptor protein LAB/NTAL. Journal of Experimental Medicine. 2004;200:991-1000.  Abstract
  • Janssen, E; Zhu, M; Zhang, W; Koonpaew, S; Zhang, W. LAB: a new membrane-associated adaptor molecule in B cell activation. Nature Immunology. 2003;4:117-123.  Abstract
  • Zhu, M; Janssen, E; Zhang, W. Minimal requirement of tyrosine residues of linker for activation of T cells in TCR signaling and thymocyte development. Journal of Immunology. 2003;170:325-333.  Abstract
  • Zhu, M; Janssen, E; Leung, K; Zhang, W. Molecular cloning of a novel gene encoding a membrane-associated adaptor protein (LAX) in lymphocyte signaling. Journal of Biological Chemistry. 2002;277:46151-46158.  Abstract
  • Zhang, W; Trible, RP; Zhu, M; Liu, SK; McGlade, CJ; Samelson, LE. Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. Journal of Biological Chemistry. 2000;275:23355-23361.  Abstract
  • Zhang, W; Sommers, CL; Burshtyn, DN; Stebbins, CC; DeJarnette, JB; Trible, RP; Grinberg, A; Tsay, HC; Jacobs, HM; Kessler, CM; Long, EO; Love, PE; Samelson, LE. Essential role of LAT in T cell development. Immunity. 1999;10:323-332.  Abstract
  • Zhang, W; Sloan-Lancaster, J; Kitchen, J; Trible, RP; Samelson, LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998;92:83-92.  Abstract
  • Zhang, W; Trible, RP; Samelson, LE. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity. 1998;9:239-246.  Abstract