Linker for activation of T cells
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Location (UCSC) | Chr 16: 28.98 – 28.99 Mb | Chr 7: 125.96 – 125.97 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
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]
Function
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]
Signaling Pathway
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]
Discovery
LAT was described in the early 1990s as a
Interactions
The Linker for Activation of T cells has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000213658 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030742 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 1806525.
- ^ a b "Entrez Gene: LAT Linker of Activated T cells".
- PMID 15081526.
- ^ PMID 26354432.
- ^ PMID 33936119.
- PMID 34897277.
- ^ PMID 23150273.
- PMID 7516467.
- PMID 9529333.
- S2CID 14131281.
- PMID 10224278.
- ^ PMID 12186560.
- ^ PMID 11368773.
- PMID 10506192.
- PMID 11279207.
- PMID 9729044.
- PMID 10488157.
- PMID 12084069.
Further reading
- Wange RL (December 2000). "LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways". Science's STKE. 2000 (63): re1. S2CID 31968793.
- Sommers CL, Samelson LE, Love PE (January 2004). "LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways". BioEssays. 26 (1): 61–67. PMID 14696041.
- Rivera J (March 2005). "NTAL/LAB and LAT: a balancing act in mast-cell activation and function". Trends in Immunology. 26 (3): 119–122. PMID 15745852.
- Trüb T, Frantz JD, Miyazaki M, Band H, Shoelson SE (January 1997). "The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling". The Journal of Biological Chemistry. 272 (2): 894–902. PMID 8995379.
- Hendricks-Taylor LR, Motto DG, Zhang J, Siraganian RP, Koretzky GA (January 1997). "SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells". The Journal of Biological Chemistry. 272 (2): 1363–1367. PMID 8995445.
- Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (January 1998). "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell. 92 (1): 83–92. S2CID 1806525.
- Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC, et al. (April 1998). "Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells". The Journal of Experimental Medicine. 187 (7): 1157–1161. PMID 9529333.
- Zhang W, Trible RP, Samelson LE (August 1998). "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity. 9 (2): 239–246. PMID 9729044.
- Finco TS, Kadlecek T, Zhang W, Samelson LE, Weiss A (November 1998). "LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway". Immunity. 9 (5): 617–626. PMID 9846483.
- Sarkar S (December 1998). "Tyrosine phosphorylation and translocation of LAT in platelets". FEBS Letters. 441 (3): 357–360. S2CID 22219232.
- Liu SK, Fang N, Koretzky GA, McGlade CJ (January 1999). "The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors". Current Biology. 9 (2): 67–75. S2CID 14131281.
- Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Irvin BJ, Zhang W, et al. (March 1999). "Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity". Journal of Immunology. 162 (5): 2453–2456. PMID 10072481.
- Zhang W, Sommers CL, Burshtyn DN, Stebbins CC, DeJarnette JB, Trible RP, et al. (March 1999). "Essential role of LAT in T cell development". Immunity. 10 (3): 323–332. PMID 10204488.
- Tang J, Sawasdikosol S, Chang JH, Burakoff SJ (August 1999). "SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9775–9780. PMID 10449770.
- Gross BS, Melford SK, Watson SP (August 1999). "Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets". European Journal of Biochemistry. 263 (3): 612–623. PMID 10469124.
- Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M (September 1999). "Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells". The Journal of Biological Chemistry. 274 (39): 28050–28057. PMID 10488157.
- Shan X, Wange RL (October 1999). "Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment". The Journal of Biological Chemistry. 274 (41): 29323–29330. PMID 10506192.
- Bosselut R, Zhang W, Ashe JM, Kopacz JL, Samelson LE, Singer A (November 1999). "Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction". The Journal of Experimental Medicine. 190 (10): 1517–1526. PMID 10562325.
- Tridandapani S, Lyden TW, Smith JL, Carter JE, Coggeshall KM, Anderson CL (July 2000). "The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells". The Journal of Biological Chemistry. 275 (27): 20480–20487. PMID 10781611.
- Zhang W, Trible RP, Zhu M, Liu SK, McGlade CJ, Samelson LE (July 2000). "Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling". The Journal of Biological Chemistry. 275 (30): 23355–23361. PMID 10811803.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.