Independent and cooperative roles of adaptor molecules in proximal signaling during FcepsilonRI-mediated mast cell activation.
Activation through FcepsilonRI, 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 Cgamma (PLCgamma). 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 FcepsilonRI in mast cells.
Kambayashi
Taku
T
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. taku.kambayashi@uphs.upenn.edu
Okumura
Mariko
M
Baker
Rebecca G
RG
Hsu
Chih-Jung
CJ
Baumgart
Tobias
T
Zhang
Weiguo
W
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D027241:Amino Acid Transport System y+L; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D017455:Receptors, IgE / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D027301:Fusion Regulatory Protein 1, Light Chains; D010750:Phosphoproteins; D017455:Receptors, IgE; C518286:SLC7A8 protein, mouse; C092947:SLP-76 signal Transducing adaptor proteins; C518287:Slc7a7 protein, mouse; D002118:Calcium