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Independent and Cooperative Roles of Adaptor Molecules in Proximal Signaling during FcRI-Mediated Mast Cell Activation
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 FcRI, a high-affinity IgE-binding receptor,is critical for mast cell function during allergy. The formationof a multimolecular proximal signaling complex nucleated bythe adaptor molecules SLP-76 and LAT1 is required for activationthrough this receptor. Based on previous T-cell studies, currentdogma dictates that LAT1 is required for plasma membrane recruitmentand function of SLP-76. Unexpectedly, we found that the recruitmentand 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 preservedmembrane localization and phosphorylation of SLP-76 in LAT1–/–mast cells. Although LAT2 supported SLP-76 phosphorylation andrecruitment to the plasma membrane, LAT2 only partially compensatedfor LAT1-mediated cell signaling due to its decreased abilityto stabilize interactions with phospholipase C (PLC). Comparisonof SLP-76–/– LAT1–/– and SLP-76–/–mast cells revealed that some functions of LAT1 could occurindependently of SLP-76. We propose that while SLP-76 and LAT1depend on each other for many of their functions, LAT2/SLP-76interactions and SLP-76-independent LAT1 functions also mediatea positive signaling pathway downstream of FcRI 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}mail.med.upenn.edu. 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}uphs.upenn.edu
Published ahead of print on 6 July 2010.
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Complementary Phosphorylation Sites in the Adaptor Protein SLP-76 Promote Synergistic Activation of Natural Killer Cells.
RI-Mediated Mast Cell Activation
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
(PLC
Published ahead of print on 6 July 2010. 
