Independent and Cooperative Roles of Adaptor Molecules in Proximal Signaling During FcepsilonRI-mediated Mast Cell Activation
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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.
Thome C, Ferreira G, Pereira-Martins D, Augusto Dos Santos G, Ortiz C, de Souza L Sci Rep. 2020; 10(1):10315.
PMID: 32587277 PMC: 7316767. DOI: 10.1038/s41598-020-66223-2.
Yablonski D Front Immunol. 2019; 10:1704.
PMID: 31402911 PMC: 6669380. DOI: 10.3389/fimmu.2019.01704.
The role of activated adenosine receptors in degranulation of human LAD2 mast cells.
Leung C, Li A, Banerjee J, Gao Z, Kambayashi T, Jacobson K Purinergic Signal. 2014; 10(3):465-75.
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Diacylglycerol kinase ζ limits the generation of natural regulatory T cells.
Schmidt A, Zou T, Joshi R, Leichner T, Pimentel M, Sommers C Sci Signal. 2013; 6(303):ra101.
PMID: 24280042 PMC: 4103616. DOI: 10.1126/scisignal.2004411.
Bounab Y, Hesse A, Iannascoli B, Grieco L, Coute Y, Niarakis A Mol Cell Proteomics. 2013; 12(10):2874-89.
PMID: 23820730 PMC: 3790297. DOI: 10.1074/mcp.M112.025908.