Biology:Linker for Activation of T cells
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The Linker for Activation of T cells, also known as Linker of Activated T cells or LAT, is a protein which in humans is encoded by the LAT gene.[1] Alternative splicing results in multiple transcript variants encoding different isoforms.[2]
Function
The protein encoded by this gene is phosphorylated by ZAP70/Syk protein tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction pathway. This 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.[3] Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement.[2]
Discovery
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.[4] 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.[1][5]
Interactions
The Linker for Activation of T cells has been shown to interact with:
- GRAP2,[6][7]
- GRAP,[1][8]
- Grb2,[1][8][9]
- ITK,[8][10]
- MAP4K1[11]
- PIK3R1,[9]
- PLCG1,[1][9][12]
- SHB,[13][14]
- VAV1,[8][9] and
- ZAP-70.[8][9]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell 92 (1): 83–92. January 1998. doi:10.1016/S0092-8674(00)80901-0. PMID 9489702.
- ↑ 2.0 2.1 "Entrez Gene: LAT Linker of Activated T cells". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27040.
- ↑ "Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling". Immunol. Lett. 92 (1–2): 43–9. 2004. doi:10.1016/j.imlet.2003.10.013. PMID 15081526.
- ↑ "GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation". Mol. Cell. Biol. 14 (7): 4435–42. 1994. PMID 7516467.
- ↑ "Molecular Cloning of the cDNA Encoding pp36, a Tyrosine-phosphorylated Adaptor Protein Selectively Expressed by T Cells and Natural Killer Cells". J. Exp. Med. 187 (7): 1157–61. 1998. doi:10.1084/jem.187.7.1157. PMID 9529333.
- ↑ "The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors". Curr. Biol. 9 (2): 67–75. Jan 1999. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361.
- ↑ "Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT". J. Exp. Med. 189 (9): 1383–90. May 1999. doi:10.1084/jem.189.9.1383. PMID 10224278.
- ↑ 8.0 8.1 8.2 8.3 8.4 "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry 41 (34): 10732–40. Aug 2002. doi:10.1021/bi025554o. PMID 12186560.
- ↑ 9.0 9.1 9.2 9.3 9.4 "Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells". Biochem. J. 356 (Pt 2): 461–71. Jun 2001. doi:10.1042/0264-6021:3560461. PMID 11368773.
- ↑ "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". J. Biol. Chem. 274 (41): 29323–30. Oct 1999. doi:10.1074/jbc.274.41.29323. PMID 10506192.
- ↑ "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". J. Biol. Chem. 276 (22): 18908–14. Jun 2001. doi:10.1074/jbc.M101485200. PMID 11279207.
- ↑ "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–46. Aug 1998. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044.
- ↑ "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". J. Biol. Chem. 274 (39): 28050–7. Sep 1999. doi:10.1074/jbc.274.39.28050. PMID 10488157.
- ↑ "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". Eur. J. Biochem. 269 (13): 3279–88. Jul 2002. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069.
Further reading
- "LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways". Sci. STKE 2000 (63): RE1. 2002. doi:10.1126/stke.2000.63.re1. PMID 11752630.
- "LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways". BioEssays 26 (1): 61–7. 2004. doi:10.1002/bies.10384. PMID 14696041.
- "NTAL/LAB and LAT: a balancing act in mast-cell activation and function". Trends Immunol. 26 (3): 119–22. 2005. doi:10.1016/j.it.2005.01.001. PMID 15745852.
- "The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling". J. Biol. Chem. 272 (2): 894–902. 1997. doi:10.1074/jbc.272.2.894. PMID 8995379.
- "SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells". J. Biol. Chem. 272 (2): 1363–7. 1997. doi:10.1074/jbc.272.2.1363. PMID 8995445.
- "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell 92 (1): 83–92. 1998. doi:10.1016/S0092-8674(00)80901-0. PMID 9489702.
- "Molecular Cloning of the cDNA Encoding pp36, a Tyrosine-phosphorylated Adaptor Protein Selectively Expressed by T Cells and Natural Killer Cells". J. Exp. Med. 187 (7): 1157–61. 1998. doi:10.1084/jem.187.7.1157. PMID 9529333.
- "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–46. 1998. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044.
- "LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway". Immunity 9 (5): 617–26. 1998. doi:10.1016/S1074-7613(00)80659-7. PMID 9846483.
- "Tyrosine phosphorylation and translocation of LAT in platelets". FEBS Lett. 441 (3): 357–60. 1999. doi:10.1016/S0014-5793(98)01584-1. PMID 9891970.
- "The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors". Curr. Biol. 9 (2): 67–75. 1999. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361.
- "Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity". J. Immunol. 162 (5): 2453–6. 1999. PMID 10072481.
- "Essential role of LAT in T cell development". Immunity 10 (3): 323–32. 1999. doi:10.1016/S1074-7613(00)80032-1. PMID 10204488.
- "SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling". Proc. Natl. Acad. Sci. U.S.A. 96 (17): 9775–80. 1999. doi:10.1073/pnas.96.17.9775. PMID 10449770.
- "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". Eur. J. Biochem. 263 (3): 612–23. 1999. doi:10.1046/j.1432-1327.1999.00560.x. PMID 10469124.
- "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". J. Biol. Chem. 274 (39): 28050–7. 1999. doi:10.1074/jbc.274.39.28050. PMID 10488157.
- "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". J. Biol. Chem. 274 (41): 29323–30. 1999. doi:10.1074/jbc.274.41.29323. PMID 10506192.
- "Association of the Adaptor Molecule Lat with Cd4 and Cd8 Coreceptors Identifies a New Coreceptor Function in T Cell Receptor Signal Transduction". J. Exp. Med. 190 (10): 1517–26. 1999. doi:10.1084/jem.190.10.1517. PMID 10562325.
- "The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells". J. Biol. Chem. 275 (27): 20480–7. 2000. doi:10.1074/jbc.M909462199. PMID 10781611.
- "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". J. Biol. Chem. 275 (30): 23355–61. 2000. doi:10.1074/jbc.M000404200. PMID 10811803.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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