The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a protein involved in the T-cell antigen receptor signal transduction pathway which in humans is encoded by the LAT gene. [5] Alternative splicing results in multiple transcript variants encoding different isoforms. [6]
The LAT protein encoded by the gene of the same name, plays a key role in the diversification of T cell signaling pathways following activation of the T-cell antigen receptor (TCR) signal transduction pathway, which is first catalyzed by TCR binding to MHC class II. LAT is a transmembrane protein localizes to lipid rafts (also known as glycosphingolipid-enriched microdomains or GEMs) and acts as a docking site for SH2 domain-containing proteins. [7] Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement. [6] In mouse thymocytes, lack of functional LAT or the inability for LAT to be phosphorylated leads to complete lack of T cell development. Moreover, mutation and deletion of LAT hampers overall TCR mediated T cell response. [8]
Prior to phosphorylation of LAT, the TCR signal transduction pathway is initiated by a TCR interacting with peptide bound MHC, and immediately leads to the activation of LCK and Fyn, which are members of the Src family of kinases. [8] Activated LCK subsequently phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) of the T-cell surface glycoprotein CD3 zeta chain, which is a protein associated with the TCR complex, in two specific locations. [9] The phosphorylated ITAMs of the CD3 zeta chain allows for ZAP-70, a Syk family protein tyrosine kinase, to bind, become activated, and phosphorylate LAT. [10]
ZAP-70 phosphorylates tyrosines on LAT, specifically tyrosines 171, 191, and 226 is able to interact with adaptor proteins that have a SH2 domain, and are members of the Grb2 protein family, such as Gads. [11] [9] Moreover, phosphorylation of LAT tyrosine 132 allows for PLCγ1-LAT association, which, when combined with concurrent Gads binding to tyrosines 171 or 191 of LAT, allows for the formation of a LAT-nucleated signaling complex. LAT-interacting Gads attracts the binding of SLP-76, which recruits additional effector molecules that assist in the stabilization of PLCγ1 binding to the LAT complex. [11] The resulting LAT signaling complex, which contains the molecules PLCγ1, Grb2, Gads, SLP-76 and the necessary associated ligands thus allow for diversification of the TCR signaling pathway through actin production, the activation of transcription factors, and other messaging signals. [11]
LAT was described in the early 1990s as a phosphoprotein of 36–38 kDa (pp. 36–38) rapidly phosphorylated on tyrosine residues following TCR ligation. [12] Cloning of the gene revealed that the protein product is a type III (leaderless) transmembrane protein of 262 aminoacids (long form) or 233 aminoacids (short form) in humans, 242 aminoacids in mouse, and 241 aminoacids in rat. [5] [13]
The Linker for Activation of T cells has been shown to interact with:
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
