T lymphocytes are the central components of immune system and signaling via the T-cell antigen receptor (TCR) plays an important role in immune responses to regulate T-cell survival, proliferation, differentiation, and effector function. LAT (linker for activation of T-cells) is a membrane-associated adaptor protein that is phosphorylated upon T-cell activation. Phosphorylated LAT associates with Grb2, Gads, PLCyl, and other signaling molecules. Current studies from LAT-deficient cells and LAT knock-out mice show that LAT is essential for TCR-mediated signal transduction and thymocyte development. We propose that, upon T-cell activation, LAT couples Ras-MAPK activation and Ca2+ flux to TCR engagement by interacting with multiple proteins. LAT interaction with other signaling proteins is also required in different stages of thymocyte development. There are three specific aims designed to test this hypothesis and to further understand how LAT functions in T-cell activation.
In specific aim 1, we will map the in vivo and in vitro tyrosine and serine/threonine phosphorylation sites of LAT. Mapping the phosphorylation sites is required to understand how other signaling proteins interact with LAT and how LAT function is regulated.
In specific aim 2, we will use different LAT mutants to dissect LAT-mediated protein complexes and to determine the importance of these complexes in TCR signaling.
In specific aim 3, we will reconstitute bone marrow cells from LAT-deficient mice with recombinant retroviruses expressing different LAT mutants and transfer these transduced cells back to LAT-deficient mice to determine LAT function in thymocyte development. Determination of LAT function and further understanding TCR signaling pathway could facilitate the design of a rational approach to augment or inhibit T-cell proliferation in autoimmunity, allergy, and tissue and organ transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Mallia, Conrad M
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Duke University
Schools of Medicine
United States
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Myers, Darienne R; Lau, Tannia; Markegard, Evan et al. (2017) Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells. Cell Rep 19:1558-1571
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Zhu, Minghua; Fuller, Deirdre M; Ou-Yang, Chih-wen et al. (2012) Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB. J Immunol 188:2733-41
Fuller, Deirdre M; Zhu, Minghua; Song, Xiaohua et al. (2012) Regulation of RasGRP1 function in T cell development and activation by its unique tail domain. PLoS One 7:e38796
Fuller, Deirdre M; Zhu, Minghua; Koonpaew, Surapong et al. (2012) The importance of the Erk pathway in the development of linker for activation of T cells-mediated autoimmunity. J Immunol 189:4005-13
Ou-Yang, Chih-wen; Zhu, Minghua; Fuller, Deirdre M et al. (2012) Role of LAT in the granule-mediated cytotoxicity of CD8 T cells. Mol Cell Biol 32:2674-84
Zhu, Minghua; Fuller, Deirdre M; Zhang, Weiguo (2012) The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development. J Biol Chem 287:8135-43

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