Linker of activated T cells
The Linker for Activation of T cells, also known as 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:
References
- ↑ 1.0 1.1 1.2 1.3 1.4 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. doi:10.1016/S0092-8674(00)80901-0. PMID 9489702.
- ↑ 2.0 2.1 "Entrez Gene: LAT Linker of Activated T cells".
- ↑ Horejsí V (2004). "Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling". Immunol. Lett. 92 (1–2): 43–9. doi:10.1016/j.imlet.2003.10.013. PMID 15081526.
- ↑ Sieh M, Batzer A, Schlessinger J, Weiss A (1994). "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. PMC 358815. PMID 7516467.
- ↑ Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC et al. (1998). "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. doi:10.1084/jem.187.7.1157. PMC 2212210. PMID 9529333.
- ↑ Liu SK, Fang N, Koretzky GA, McGlade CJ (Jan 1999). "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. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361.
- ↑ Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N et al. (May 1999). "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. doi:10.1084/jem.189.9.1383. PMC 2193052. PMID 10224278.
- ↑ 8.0 8.1 8.2 8.3 8.4 Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K et al. (Aug 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry 41 (34): 10732–40. doi:10.1021/bi025554o. PMID 12186560.
- ↑ 9.0 9.1 9.2 9.3 9.4 Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A (Jun 2001). "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. doi:10.1042/0264-6021:3560461. PMC 1221857. PMID 11368773.
- ↑ Shan X, Wange RL (Oct 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". J. Biol. Chem. 274 (41): 29323–30. doi:10.1074/jbc.274.41.29323. PMID 10506192.
- ↑ Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR et al. (Jun 2001). "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". J. Biol. Chem. 276 (22): 18908–14. doi:10.1074/jbc.M101485200. PMID 11279207.
- ↑ Zhang W, Trible RP, Samelson LE (Aug 1998). "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–46. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044.
- ↑ Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M (Sep 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". J. Biol. Chem. 274 (39): 28050–7. doi:10.1074/jbc.274.39.28050. PMID 10488157.
- ↑ Lindholm CK, Henriksson ML, Hallberg B, Welsh M (Jul 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". Eur. J. Biochem. 269 (13): 3279–88. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069.
Further reading
- Wange RL (2002). "LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways". Sci. STKE 2000 (63): RE1. doi:10.1126/stke.2000.63.re1. PMID 11752630.
- Sommers CL, Samelson LE, Love PE (2004). "LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways". BioEssays 26 (1): 61–7. doi:10.1002/bies.10384. PMID 14696041.
- Rivera J (2005). "NTAL/LAB and LAT: a balancing act in mast-cell activation and function". Trends Immunol. 26 (3): 119–22. doi:10.1016/j.it.2005.01.001. PMID 15745852.
- Trüb T, Frantz JD, Miyazaki M, Band H, Shoelson SE (1997). "The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling". J. Biol. Chem. 272 (2): 894–902. doi:10.1074/jbc.272.2.894. PMID 8995379.
- Hendricks-Taylor LR, Motto DG, Zhang J, Siraganian RP, Koretzky GA (1997). "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. doi:10.1074/jbc.272.2.1363. PMID 8995445.
- Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (1998). "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell 92 (1): 83–92. doi:10.1016/S0092-8674(00)80901-0. PMID 9489702.
- Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC et al. (1998). "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. doi:10.1084/jem.187.7.1157. PMC 2212210. PMID 9529333.
- Zhang W, Trible RP, Samelson LE (1998). "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–46. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044.
- Finco TS, Kadlecek T, Zhang W, Samelson LE, Weiss A (1998). "LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway". Immunity 9 (5): 617–26. doi:10.1016/S1074-7613(00)80659-7. PMID 9846483.
- Sarkar S (1999). "Tyrosine phosphorylation and translocation of LAT in platelets". FEBS Lett. 441 (3): 357–60. doi:10.1016/S0014-5793(98)01584-1. PMID 9891970.
- Liu SK, Fang N, Koretzky GA, McGlade CJ (1999). "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. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361.
- Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Irvin BJ, Zhang W et al. (1999). "Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity". J. Immunol. 162 (5): 2453–6. PMID 10072481.
- Zhang W, Sommers CL, Burshtyn DN, Stebbins CC, DeJarnette JB, Trible RP et al. (1999). "Essential role of LAT in T cell development". Immunity 10 (3): 323–32. doi:10.1016/S1074-7613(00)80032-1. PMID 10204488.
- Tang J, Sawasdikosol S, Chang JH, Burakoff SJ (1999). "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. doi:10.1073/pnas.96.17.9775. PMC 22286. PMID 10449770.
- Gross BS, Melford SK, Watson SP (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". Eur. J. Biochem. 263 (3): 612–23. doi:10.1046/j.1432-1327.1999.00560.x. PMID 10469124.
- Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M (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". J. Biol. Chem. 274 (39): 28050–7. doi:10.1074/jbc.274.39.28050. PMID 10488157.
- Shan X, Wange RL (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". J. Biol. Chem. 274 (41): 29323–30. doi:10.1074/jbc.274.41.29323. PMID 10506192.
- Bosselut R, Zhang W, Ashe JM, Kopacz JL, Samelson LE, Singer A (1999). "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. doi:10.1084/jem.190.10.1517. PMC 2195704. PMID 10562325.
- Tridandapani S, Lyden TW, Smith JL, Carter JE, Coggeshall KM, Anderson CL (2000). "The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells". J. Biol. Chem. 275 (27): 20480–7. doi:10.1074/jbc.M909462199. PMID 10781611.
- Zhang W, Trible RP, Zhu M, Liu SK, McGlade CJ, Samelson LE (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". J. Biol. Chem. 275 (30): 23355–61. 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.