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Mol. Cell. Biol. 30 (17): 4188-4196

Copyright © 2010 by the American Society for Microbiology. All rights reserved.

Independent and Cooperative Roles of Adaptor Molecules in Proximal Signaling during Fc{varepsilon}RI-Mediated Mast Cell Activation{triangledown}

Taku Kambayashi,1,2* Mariko Okumura,1,2 Rebecca G. Baker,1 Chih-Jung Hsu,3 Tobias Baumgart,3 Weiguo Zhang,4, and Gary A. Koretzky1,5*

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,1 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,2 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania,3 Department of Immunology, Duke University Medical Center, Durham, North Carolina,4 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania5

Received for publication 17 March 2010. Revision received 5 April 2010. Accepted for publication 16 June 2010.

Abstract: Activation through Fc{varepsilon}RI, a high-affinity IgE-binding receptor, is critical for mast cell function during allergy. The formation of a multimolecular proximal signaling complex nucleated by the adaptor molecules SLP-76 and LAT1 is required for activation through this receptor. Based on previous T-cell studies, current dogma dictates that LAT1 is required for plasma membrane recruitment and function of SLP-76. Unexpectedly, we found that the recruitment and phosphorylation of SLP-76 were preserved in LAT1–/– mast cells and that SLP-76–/– and LAT1–/– mast cells harbored distinct functional and biochemical defects. The LAT1-like molecule LAT2 was responsible for the preserved membrane localization and phosphorylation of SLP-76 in LAT1–/– mast cells. Although LAT2 supported SLP-76 phosphorylation and recruitment to the plasma membrane, LAT2 only partially compensated for LAT1-mediated cell signaling due to its decreased ability to stabilize interactions with phospholipase C{gamma} (PLC{gamma}). Comparison of SLP-76–/– LAT1–/– and SLP-76–/– mast cells revealed that some functions of LAT1 could occur independently of SLP-76. We propose that while SLP-76 and LAT1 depend on each other for many of their functions, LAT2/SLP-76 interactions and SLP-76-independent LAT1 functions also mediate a positive signaling pathway downstream of Fc{varepsilon}RI in mast cells.

* Corresponding author. Mailing address for Gary A. Koretzky: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III, Room 415, 421 Curie Boulevard, Philadelphia, PA 19104-6160. Phone: (215) 746-5522. Fax: (215) 746-5525. E-mail: koretzky{at} Mailing address for Taku Kambayashi: Department of Pathology and Laboratory Medicine, University of Pennsylvania, 288 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6160. Phone: (215) 746-7610. Fax: (215) 573-9261. E-mail: taku.kambayashi{at}

{triangledown} Published ahead of print on 6 July 2010.

Diacylglycerol Kinase {zeta} Limits the Generation of Natural Regulatory T Cells.
A. M. Schmidt, T. Zou, R. P. Joshi, T. M. Leichner, M. A. Pimentel, C. L. Sommers, and T. Kambayashi (2013)
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Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function.
R. M. May, M. Okumura, C.-J. Hsu, H. Bassiri, E. Yang, G. Rak, E. M. Mace, N. H. Philip, W. Zhang, T. Baumgart, et al. (2013)
Blood 121, 3135-3146
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SLP-76 is required for high-affinity IgE receptor- and IL-3 receptor-mediated activation of basophils.
S. Hidano, D. Kitamura, L. Kumar, R. S. Geha, and R. Goitsuka (2012)
Int. Immunol. 24, 719-727
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Complementary Phosphorylation Sites in the Adaptor Protein SLP-76 Promote Synergistic Activation of Natural Killer Cells.
H. S. Kim and E. O. Long (2012)
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Immunoglobulin E Receptor Signaling and Asthma.
L. C. Wu (2011)
J. Biol. Chem. 286, 32891-32897
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Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells.
M. Sela, Y. Bogin, D. Beach, T. Oellerich, J. Lehne, J. E. Smith-Garvin, M. Okumura, E. Starosvetsky, R. Kosoff, E. Libman, et al. (2011)
EMBO J. 30, 3160-3172
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