Disease relevance of LAT

• The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation [1].
• We present our experience concerning LAT expression in both neoplastic and inflammatory dermatoses using an immunohistochemical approach on frozen sections from 42 patients [2].
• More recently, LAT "knock-ins" harboring point mutations in the four COOH-terminal tyrosine residues, were found to develop lymphoproliferative disorders involving polyclonal T cells that produced high amounts of T helper-type 2 (Th2) cytokines [3].
• Moreover, other elements of the pre-TCR/TCR signaling pathway, like LAT and Lck, were also found in B-ALL cells [4].
• The LAT-Nef protein was more efficient than its nonraft mutant counterpart at downmodulating both cell surface CD4 and class I major histocompatibility complex (MHC) expression, as well as in enhancing first-round infectivity and being incorporated into virus particles [5].

Psychiatry related information on LAT

• As phenylalanine excess in the brain leads to mental retardation in untreated patients with phenylketonuria, mutations of the LAT1 gene can be responsible for milder clinical manifestations (lower brain toxicity of hyperphenylalaninaemia) observed in some patients [6].

High impact information on LAT

• Using a two color imaging approach that allows tracking of single molecules relative to the CD2/LAT/Lck clusters, we demonstrate that these microdomains exclude and limit the free diffusion of molecules in the membrane but also can trap and immobilize specific proteins [7].
• These microdomains require protein-protein interactions mediated through phosphorylation of LAT and are not maintained by interactions with actin or lipid rafts [7].
• LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation [8].
• Therefore, we propose to name the molecule LAT-linker for activation of T cells [8].
• By similar criteria, we determine that lipocortin II is the human analogue of pp36, a major substrate for pp60src, which has been characterized in chicken embryo fibroblasts and in bovine brush border preparations [9].

Chemical compound and disease context of LAT

• Furthermore, among the proteins of the TCR signaling pathway, the tyrosine phosphorylation levels of LAT and SLP-76 are the most affected in T cells exposed to low numbers of Yersinia pseudotuberculosis [1].
• We exploited Jurkat leukemia T cell clone E6-1 as a model of Trichostatin A (TSA) effect on cellular levels of ZAP-70, LAT and SLP-76 molecules involved in the signal transduction pathway from T cell receptor to nucleus [10].
• If the LAT was used in conjunction with the tests of indole production or lactose fermentation, the specificity values for the identification of Escherichia coli increased from 93.3 to 98.8 and 98.7%, respectively [11].
• If the LAT, indole production, and lactose fermentation were used together for the identification of Escherichia coli, the sensitivity and specificity were 94 and 99.7%, respectively [11].

Biological context of LAT

• Measured calorimetrically, Gads-SH2 binds LAT tyrosine phosphorylation sites 171 and 191 with higher affinities than the other sites, with the differences ranging from only several fold weaker binding to no detectable interaction [12].
• Human LAT contains five potential binding sites for Gads, of which only those at Tyr171 and Tyr191 appear necessary for T-cell function [12].
• The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells [13].
• It shares no overall sequence homology with LAT and is not localized to lipid rafts [14].
• Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain [15].

Anatomical context of LAT

• SLP-76 and LAT are cell-type-specific adaptor proteins expressed in T cells, NK cells, platelets, and mast cells [16].
• Here we describe the identification and preliminary characterization of a novel transmembrane adaptor protein that is structurally and evolutionarily related to LAT and is expressed in B lymphocytes, natural killer (NK) cells, monocytes, and mast cells but not in resting T lymphocytes [17].
• In transiently transfected COS-7 cells, SLAP forms separate complexes with ZAP-70, Syk, and LAT through its Src homology 2 domain [18].
• Here we used biochemical analysis of immunoisolated plasma membrane domains and fluorescence imaging of green fluorescence protein-tagged signaling proteins to investigate the contributions of different tyrosine-based signaling protein docking sites of LAT to the formation of LAT signaling protein assemblies in TCR membrane domains [19].
• Clustering of FcgammaRs on the human monocytic cell line, THP-1, induces phosphorylation of a major 36-kDa protein which immunoreacts with anti-LAT antisera [13].

Associations of LAT with chemical compounds

• We mapped the tyrosine residues in LAT responsible for interaction with these specific signaling molecules by expressing LAT mutants with tyrosine to phenylalanine mutations in LAT-deficient cells [20].
• In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca(2+) flux, and activation of AP-1 and NF-AT [20].
• The decreased mobility in patches was dependent on raft organization supported by membrane cholesterol and signaling molecule binding sites, especially the phospholipase C gamma 1 binding site in the cytoplasmic domain of LAT [21].
• Reduced intracellular levels of the antioxidant glutathione (GSH), a hallmark of chronic oxidative stress, resulted in the membrane displacement of LAT, abrogated TCR-mediated signaling and consequently hyporesponsiveness of T lymphocytes [22].
• Targeted mutation of redox-sensitive cysteine residues within LAT created LAT mutants which remain membrane anchored under conditions of chronic oxidative stress [22].

Physical interactions of LAT

• Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain [23].
• Phosphorylated LAT binds Grb2, PLC-gamma1, and other signaling molecules [24].
• Taken together, these results suggest that, unlike the non-raft pool, CD38 in rafts is able to initiate and propagate several activating signaling pathways, possibly by facilitating critical associations within other raft subsets, for example, LAT rafts via its capacity to interact with Lck and CD3-zeta [25].

Enzymatic interactions of LAT

• The endocytosed SLP-76 clusters contained phosphorylated SLP-76 and phosphorylated LAT [26].

Regulatory relationships of LAT

• Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways [15].
• These data reveal LAT displacement from lipid rafts as a molecular mechanism by which PUFAs inhibit T cell signaling and underline the predominant importance of LAT localization in rafts for efficient T cell activation [27].
• In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins [28].
• The recruitment of Nck and WASp depended on TCR-induced tyrosine phosphorylation and the LAT and SLP-76 adaptors [29].
• We show in the present report that CD28 ligation induces tyrosine phosphorylation of LAT [30].

Other interactions of LAT

• We observed that SLAP is expressed in T cells, and upon TCR activation, SLAP interacts with ZAP-70, Syk, LAT, and TCRzeta chain in Jurkat T cells [18].
• However, phospholipase Cgamma1 (PLCgamma1) and LAT were strikingly hypophosphorylated in CD148-expressing cells following TCR stimulation, whereas the phosphorylation levels of Slp-76 and Itk were modestly reduced [31].
• These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation [32].
• Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation [31].
• NTAL (non-T cell activation linker)/LAB (linker for activation of B cells) is a LAT (linker for activation of T cells)-like molecule that is expressed in B cells, mast cells, natural killer cells, and monocytes [33].

Analytical, diagnostic and therapeutic context of LAT

• The LAT1 cDNA was amplified by PCR using two sets of primers (one specific for rat LAT1 and another simultaneously specific for human, rat and mice) [34].
• We have mapped the LAT gene by radiation hybrid mapping and fluorescence in situ hybridization to chromosome 16p11 [35].
• Proteins in the lipid raft and nonraft fractions were analyzed by Western blotting and probed for phosphotyrosine activity and for LCK, LAT, and CD3 epsilon [36].
• To demonstrate the practical potential and limitations of global analyses of ITC titrations for the study of cooperative multiprotein interactions, we have examined the interactions of three proteins that are critical for signal transduction after T-cell activation, LAT, Grb2, and Sos1 [37].
• Association of pp36/38 with PI-3-K p85 was confirmed by transfection of a hemagglutinin-tagged p85 alpha cDNA into Jurkat cells followed by anti-hemagglutinin immunoprecipitation [38].

References