Linker-for-activation of T cells (LAT) protein (Linker_for_activat_Tcells_prot)
Type: Family

A key event in the regulation of the adaptive immune response is the binding of major histocompatibility complex (MHC)-peptide complexes to T cell antigen receptors (TCRs). The formation of such ternary complexes induces significant biochemical changes within T cells of the host animal. The first detectable response of the T cell is the rapid accumulation of numerous tyrosine-phosphorylated proteins within the cell. Increased phosphotyrosine occurs as a consequence of the activation of several different TCR-associated, hematopoietic-specific protein kinases (PTKs), thereby perturbing the balance between those enzymes that add, and those that remove, phosphates from key tyrosine residues. These initial phosphorylation events are required for the subsequent activation of the small guanosine triphosphatase (GTPase) proteins Ras and Rac, the lipid kinase P13K and PLC-gamma1. Activation of these cytoplasmic signalling proteins ultimately leads to activation of various transcription factors (NF-AT, NF-kB, and AP-1) and increased transcription from genes that have an important role in initiating T cell proliferation, such as interleukin-2 (IL-2) .

An unresolved question in the field has been which molecules and what sequence of events tie together the early tyrosine phosphorylation events with the activation of these downstream signalling molecules. A likely candidate for linking the proximal and distal portions of the TCR signalling pathway is a 36kDa transmembrane protein termed LAT. LAT becomes phosphorylated after TCR engagement, thereby creating binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2, Gads, Grap, 3BP2 and Shb. It also indirectly binds SOS, c-Cbl, Vav, SLP-76 and Itk.

LAT is expressed in peripheral blood lymphocytes, thymus and spleen, as well as in other blood cells, including megakaryocytes, platelets, natural killer cells and mast cells. It is excluded from the cytosol, and is found at the plasma membrane and in the perinuclear compartment. The cellular localisation of LAT seems to be extremely sensitive to alternations in the intracellular redox balance. Reduced intracellular levels of antioxidants result in the membrane displacement of LAT (a consequence of a conformational change interfering with its insertion into the membrane), abrogation of TCR-mediated signalling and, consequently, hyporesponsiveness of T lymphocytes.

The amino acid sequence of LAT contains no recognised functional domains, but, consistent with its strong tyrosine phosphorylation upon TCR stimulation, its predicted cytoplasmic tail contains 10 tyrosines, 9 of which are conserved between mouse, rat and human proteins. In addition, LAT also has 2 cysteine residues (Cys26 and Cys29 in human) that are conserved among human, rat, mouse and bovine proteins. These residues lie proximal to the inner face of the plasma membrane: Cys26 within the TM region and Cys29 located juxtamembrane. These membrane-proximal residues are thought to play a vital role in LAT function. In fact, LAT is subject to post-translational palmitoylation of these residues, which appears to be necessary to target LAT to lipid rafts in the membrane, where it can recruit key cytosolic signalling proteins to the aggregated rafts upon TCR stimulation. Raft membrane domains are envisaged as lateral assemblies of sphingolipids and cholesterol that form ordered membrane phases .