Abstract

EXCEED THE SPACE PROVIDED. Engagement of antigen receptors on T and B cells leads to activation of a series of signaling cascades, including phosphorylation of cellular proteins and activation of the Ras-MAPK pathway and Ca 2+ flux. In T cells, the membrane-associated adaptor molecule, LAT (Linker for activation ofT cells), plays a crucial role in connecting the TCR engagement to Ras-MAPK activation and Ca 2+ flux by recruiting Grb2, Gads, and PLC-y1 to the membrane. However, it is not clear how the BCR engagement is coupled to Ras-MAPK activation and Ca 2 flux. A LAT-like molecule has not been found in B cells. Recently, we cloned a novel gene encoding a membrane-associated adaptor protein. We named this gene, LAB (Linker for activation of B cells). Our preliminary data showed that LAB shares many characteristics with LAT. We hypothesize that, in B cells, LAB functions to couple the BCR engagement to downstream Ras-MAPK activation and Ca 2+ flux by recruiting Grb2 to the membrane. This proposal aims to further study LAB function in B cell activation and development.
Three specific aims are designed to test this hypothesis.
In specific aim 1, LAB gene will be disrupted in the chicken DT40 B cell line. Signaling defects caused by deletion of this gene will be characterized.
In specific aim 2, we will examine the functional differences between LAB and LAT using transgenic mice.
In specific aim 3, LAB gene will be disrupted in mice to study LAB function in B cell development. We will also study LAB function in platelets and NK cells. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056156-03
Application #
6825768
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mallia, Conrad M
Project Start
2003-06-15
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$346,500
Indirect Cost

  Institution

Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

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
Markegard, Evan; Trager, Evan; Yang, Chih-wen Ou et al. (2011) Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCR? gene expression. PLoS One 6:e25540
Fuller, Deirdre M; Zhu, Minghua; Ou-Yang, Chih-Wen et al. (2011) A tale of two TRAPs: LAT and LAB in the regulation of lymphocyte development, activation, and autoimmunity. Immunol Res 49:97-108
Shen, Shudan; Chuck, Mariana I; Zhu, Minghua et al. (2010) The importance of LAT in the activation, homeostasis, and regulatory function of T cells. J Biol Chem 285:35393-405
Whittaker, Gillian C; Orr, Selinda J; Quigley, Laura et al. (2010) The linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) regulates triggering receptor expressed on myeloid cells (TREM)-2 signaling and macrophage inflammatory responses independently of the linker for activation of T cells. J Biol Chem 285:2976-85
Kambayashi, Taku; Okumura, Mariko; Baker, Rebecca G et al. (2010) Independent and cooperative roles of adaptor molecules in proximal signaling during FcepsilonRI-mediated mast cell activation. Mol Cell Biol 30:4188-96

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