Linker for activation of T cells

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.[5] Alternative splicing results in multiple transcript variants encoding different isoforms.[6]

LAT
Identifiers
Aliases	LAT, Lat, LAT1, pp36, linker for activation of T-cells, IMD52, linker for activation of T cells
External IDs	OMIM: 602354 MGI: 1342293 HomoloGene: 7811 GeneCards: LAT
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p11.2 Start 28,984,826 bp[1] End 28,990,783 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F3 Start 126,363,824 bp[2] End 126,369,570 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • protein kinase binding • Ras guanyl-nucleotide exchange factor activity Cellular component • integral component of membrane • membrane • intercellular junction • mast cell granule • immunological synapse • membrane raft • COP9 signalosome • Golgi apparatus • cell membrane Biological process • GO:0007243 intracellular signal transduction • adaptive immune response • gene expression • homeostasis of number of cells • regulation of T cell activation • immune system process • lymphocyte homeostasis • MAPK cascade • Fc-epsilon receptor signaling pathway • immune response • integrin-mediated signaling pathway • mast cell degranulation • inflammatory response • T cell receptor signaling pathway • T cell activation • calcium-mediated signaling • signal transduction • positive regulation of protein kinase activity • Ras protein signal transduction • positive regulation of signal transduction Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	27040	16797
Ensembl	ENSG00000213658	ENSMUSG00000030742
UniProt	O43561	O54957
RefSeq (mRNA)	NM_001014987 NM_001014988 NM_001014989 NM_014387	NM_010689
RefSeq (protein)	NP_001014987 NP_001014988 NP_001014989 NP_055202	NP_034819
Location (UCSC)	Chr 16: 28.98 – 28.99 Mb	Chr 7: 126.36 – 126.37 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[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]

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.[8] 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.[5][9]

Interactions

The Linker for Activation of T cells has been shown to interact with:

• GRAP2,[10][11]
• GRAP,[5][12]
• Grb2,[5][12][13]
• ITK,[12][14]
• MAP4K1[15]
• PIK3R1,[13]
• PLCG1,[5][13][16]
• SHB,[17][18]
• VAV1,[12][13] and
• ZAP-70.[12][13]

References

1. GRCh38: Ensembl release 89: ENSG00000213658 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000030742 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. "Entrez Gene: LAT Linker of Activated T cells".
7. 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.
8. 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. doi:10.1128/MCB.14.7.4435. PMC 358815. PMID 7516467.
9. Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC, Taskén K, Imboden JB, Vaage JT (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.
10. 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.
11. Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N, Takeshita T, Tsuchiya S, Konno T, Sugamura K (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.
12. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB (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.
13. 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.
14. 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.
15. Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, Hu MC, Wange RL, Tan TH (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.
16. 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.
17. 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.
18. 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, Taskén K, Imboden JB, Vaage JT (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, Samelson LE, Abraham RT, Leibson PJ (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, Grinberg A, Tsay HC, Jacobs HM, Kessler CM, Long EO, Love PE, Samelson LE (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. Bibcode:1999PNAS...96.9775T. 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.