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The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation

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Abstract T cells are essential for the adaptive immune response to pathogens. However, dysfunctional T cell activity has been implicated in numerous diseases, including the failure of organ transplants, allergic reactions, asthma, autoimmune disorders, and coronary artery disease. T cell responses to pathogens require the induction of the primary activating receptor, the T cell receptor (TCR), along with other costimulatory and adhesion receptors. Signal transduction pathways activated downstream of these receptors drive T cell responses required for the immune response and disease progression. A key question in our understanding of the mechanism of T cell activation is how signaling pathways emanating from multiple receptors integrate together to alter T cell effector functions. One integration node for intracellular signaling is the membrane‐associated adaptor protein linker for the activation of T cells or LAT. Upon stimulation of the TCR and other receptors, LAT is phosphorylated at several tyrosines residues on its cytoplasmic tail. This leads to the binding of SH2 domain‐containing proteins and their associated molecules and the formation of large multiprotein complexes. These dynamic and highly regulated signaling complexes facilitate the production of second messengers, activate downstream pathways, induce actin cytoskeleton polymerization, and stimulate the activity of multiple transcription factors. Thus, signaling pathways from several receptors feed into LAT, which then integrates this information and selectively induces pathways critical for T cell activation and the adaptive immune response. WIREs Syst Biol Med 2013, 5:101–110. doi: 10.1002/wsbm.1194 This article is categorized under: Biological Mechanisms > Cell Signaling

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Receptor‐mediated induction of LAT (Linker for Activation of T cells) phosphorylation. T cell receptor (TCR) and CD2 induction results in the receptor localization and/or activation of the Src family kinases Lck and Fyn. The kinases then phosphorylate ITAM motifs on the TCR. This leads to the recruitment and activation of ZAP‐70 and this kinase subsequently phosphorylates LAT. Activation of CD5, CD9, and CD28 enhances TCR‐mediated LAT phosphorylation via an unknown mechanism. CD28 induction alone is also capable of inducing LAT phosphorylation by an uncharacterized mechanism.

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Grb2/SH3 domain ligand complexes facilitate LAT (Linker for Activation of T cells) clustering. Phosphorylated LAT is capable of simultaneously binding three Grb2 proteins. At the same time, Grb2 is dimerized by its SH3 domain ligands Sos1 and c‐Cbl. The ability to bind multiple Grb2 molecules and the dimerization of Grb2 leads to the formation of a lattice of LAT that drives LAT clustering.

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Recruitment of Grb2‐mediated complexes to LAT. LAT (Linker for Activation of T cells) phosphorylation induces the binding of Grb2 to LAT Y171, Y191, and Y226. Grb2 simultaneously recruits several SH3 domain ligands to LAT. These include Sos1 and Sos2, which activated the MAP kinase pathway, c‐Cbl, which facilitates the ubiquitination of multiple signaling proteins, and Gab2, which recruits and activates the phosphatase SHP‐2 and inhibits the Gads/SLP‐76 complex.

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Recruitment of complexes containing PLCγ1, Gads, and SLP‐76 to LAT (Linker for Activation of T cells). LAT phosphorylation results in the binding of PLCγ1 to LAT Y132 and Gads to LAT Y171 or Y191. Gads also binds to SLP‐76, which stabilizes the interaction of PLCγ1 with LAT. PLCγ1 cleaves PIP2 into IP3, which induces calcium influx, and DAG, which activates RasGRP and PKC isoforms. SLP‐76 is phosphorylated by ZAP‐70 and subsequently binds ITK, which phosphorylates and activates PLCγ1, and Vav and Nck, which are critical for actin polymerization. SLP‐76 is also required for the induction of PI3 kinase, resulting in the induction of numerous downstream pathways.

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