Lots of LATs

Science Signaling  17 Aug 2010:
Vol. 3, Issue 135, pp. ec254
DOI: 10.1126/scisignal.3135ec254

The receptor at the heart of the wheezing and sniffling from allergies (and more serious symptoms that can even be deadly) is the high-affinity immunoglobulin E (IgE)–binding receptor FcεRI. Signaling mechanisms of this receptor on mast cells that bind to IgE complexes bound to antigen are thus of particular interest and medical relevance. Kambayashi et al. show that, although the signaling mechanisms of FcεRI are in general similar to those of the T cell receptor and use the same or similar proteins, there are some important functional differences in how these receptors couple to the pathways they activate. In T cells, the adaptor protein linker of activated T cells 1 (LAT1) binds to phosphotyrosine residues on the activated receptor and recruits another linker protein, SLP-76 [Src homology 2 (SH2) domain–containing leukocyte phosphoprotein of 76 kD]. In T cells, loss of SLP-76 or LAT1 causes a similar phenotype, consistent with a primary role of LAT1 in recruitment of SLP-76 to the receptor complex at the plasma membrane and cooperative binding and activation of phospholipase C, leading to sustained calcium signaling. But in the mouse mast cell studied by Kambayashi et al., localization of SLP-76 to the plasma membrane and its phosphorylation were normal in cells lacking LAT1, and the signaling defects were less pronounced than those in cells lacking SLP-76. Further analysis of cells from knockout animals showed that a related protein, LAT2, which is not expressed in naïve T cells, appears to substitute for LAT1 in terms of recruitment of SLP-76 but to be less effective in cooperating with SLP-76 in sustaining calcium signaling through interactions with phospholipase C. Elimination of SLP-76 or LAT1 in mast cells did not affect signaling to ERKs (extracellular signal–regulated kinases), but loss of both proteins did, indicating independent contributions of each protein to ERK signaling in mast cells. Comparison of cells from animals lacking LAT1 with those of animals lacking both LAT1 and SLP-76 indicated that there are SLP-76–independent signals promoted by LAT1. Thus, subtle differences in the expression of adaptor proteins, their interactions, and their independent functions distinguish signaling in T cells and mast cells.

T. Kambayashi, M. Okumura, R. G. Baker, C.-J. Hsu, T. Baumgart, W. Zhang, G. A. Koretzky, Independent and cooperative roles of adaptor molecules in proximal signaling during FcεRI-mediated mast cell activation. Mol. Cell. Biol. 30, 4188–4196 (2010). [Abstract] [Full Text]