The Journal of Experimental Medicine
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Published online 11 October 2004 doi:10.1084/jem.20041223
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 991-1000
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Positive and Negative Regulation of Fc{varepsilon}RI-Mediated Signaling by the Adaptor Protein LAB/NTAL

Minghua Zhu, Yan Liu, Surapong Koonpaew, Olivia Granillo, and Weiguo Zhang

Department of Immunology, Duke University Medical Center, Durham, NC 27710

Address correspondence to Weiguo Zhang, Duke University Medical Center, Box 3010, Durham, NC 27710. Phone: (919) 613-7803; Fax: (919) 684-8982; email: zhang033{at}mc.duke.edu

Linker for activation of B cells (LAB, also called NTAL; a product of wbscr5 gene) is a newly identified transmembrane adaptor protein that is expressed in B cells, NK cells, and mast cells. Upon BCR activation, LAB is phosphorylated and interacts with Grb2. LAB is capable of rescuing thymocyte development in LAT-deficient mice. To study the in vivo function of LAB, LAB-deficient mice were generated. Although disruption of the Lab gene did not affect lymphocyte development, it caused mast cells to be hyperresponsive to stimulation via the Fc{varepsilon}RI, evidenced by enhanced Erk activation, calcium mobilization, degranulation, and cytokine production. These data suggested that LAB negatively regulates mast cell function. However, mast cells that lacked both linker for activation of T cells (LAT) and LAB proteins had a more severe block in Fc{varepsilon}RI-mediated signaling than LAT–/– mast cells, demonstrating that LAB also shares a redundant function with LAT to play a positive role in Fc{varepsilon}RI-mediated signaling.

Key Words: LAT • MAPK • calcium flux • degranulation • mast cells

Abbreviations used in this paper: BMMC, BM-derived mast cell; DAG, diacylglycerol; ES, embryonic stem; ITAM, immunoreceptor tyrosine-based activation motif; LAB, linker for activation of B cells; LAT, linker for activation of T cells; MAPK, mitogen-activated protein kinase; NTAL, non–T cell activation linker; PTK, protein tyrosine kinase.


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