LAT, the Linker for Activation of T Cells: A Bridge Between T Cell-Specific and General Signaling Pathways

A key event in the regulation of the adaptive immune response is the binding of major histocompatibility complex-bound foreign peptides to T cell antigen receptors (TCRs) that are present on the cell surface of T lymphocytes. Recognition of the presence of cognate antigen in the host animal induces a series of biochemical changes within the T cell; these changes, in the context of additional signals from other surface receptors, ultimately result in massive proliferation of receptor-engaged T cells and the acquisition of effector and memory functions. Early studies established the importance of the activation of the enzymes phospholipase C-γ1 (PLC-γ1) and phosphatidylinositol 3-kinase (PI3K), as well as the small molecular weight heterotrimeric guanine nucleotide binding protein (G protein) Ras, in this process. These biochemical events are dependent on the activity of several protein tyrosine kinases that become activated immediately upon TCR engagement. 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 signaling molecules. A likely candidate for linking the proximal and distal portions of the TCR signaling pathway is the recently described protein, LAT. LAT is a 36-kD transmembrane protein that becomes rapidly tyrosine-phosphorylated after TCR engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-γ1, Grb2, Gads, Grap, 3BP2, and Shb, and indirectly binds SOS, c-Cbl, Vav, SLP-76, and Itk. LAT is localized to the glycolipid-enriched membrane (GEM) subdomains of the plasma membrane by virtue of palmitoylation of two cysteine residues positioned near the endofacial side of the plasma membrane. Notably, in the absence of LAT, TCR engagement does not lead to activation of distal signaling events. This review examines the circumstances surrounding the discovery of LAT and our current understanding of its properties, and discusses current models for how LAT may be functioning to support the transduction of TCR-initiated, T cell-specific signaling events to the distal, general signaling machinery. One of the unresolved questions in T cell receptor (TCR) signaling has been how T cell-specific, TCR-proximal signaling events, such as the activation of the protein tyrosine kinases (PTKs) Lck, Fyn, ZAP-70, Itk, and Tec, lead to the activation of distal, more general signaling elements, such as phospholipase C-γ1 (PLC-γ1), Ras, and phosphatidylinositol 3-kinase (PI3K). With the discovery of LAT, we are much closer to understanding how this occurs. LAT is a 36-kD transmembrane protein that is targeted to lipid rafts and is rapidly tyrosine-phosphorylated after TCR stimulation. LAT appears to serve as a hub between the proximal and distal TCR signaling pathways by facilitating the formation of multimolecular signaling complexes in response to the activation of TCR-associated PTKs. These LAT-assembled complexes are probably involved in ordering interacting proteins into a favorable geometry for productive interaction with one another. In addition to serving as an organizing nucleation scaffold, LAT also serves to localize multiple cytosolic signaling proteins to lipid rafts. Recruitment of signaling proteins to the lipid rafts leads to a very high effective local concentration of these proteins relative to each other, facilitating the formation of additional protein-protein interactions and enhancing enzymatic reaction rates. In addition, LAT-mediated targeting to the lipid rafts may serve to localize enzymes, such as PLC-γ1, PI3K, and SOS, to the vicinity of their substrates. Although it remains to be determined how much of a contribution each of these potential mechanisms makes toward LAT's signal transduction capabilities, the discovery and characterization of LAT has considerably advanced our understanding of the ever more complex series of biochemical events that link TCR engagement with T cell activation.