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Linker for activation of T cells

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LAT
Identifiers
AliasesLAT, Lat, LAT1, pp36, linker for activation of T-cells, IMD52, linker for activation of T cells
External IDsOMIM: 602354; MGI: 1342293; HomoloGene: 7811; GeneCards: LAT; OMA:LAT - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 7: 125.96 – 125.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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 phosphoprotein of 36–38 kDa (pp. 36–38) rapidly phosphorylated on tyrosine residues following TCR ligation.[12] 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][13]

Interactions

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000213658 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c d e 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. S2CID 1806525.
  6. ^ a b "Entrez Gene: LAT Linker of Activated T cells".
  7. ^ Horejsí V (March 2004). "Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling". Immunology Letters. 92 (1–2): 43–49. doi:10.1016/j.imlet.2003.10.013. PMID 15081526.
  8. ^ a b Balagopalan L, Kortum RL, Coussens NP, Barr VA, Samelson LE (October 2015). "The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters". The Journal of Biological Chemistry. 290 (44): 26422–26429. doi:10.1074/jbc.R115.665869. PMC 4646300. PMID 26354432.
  9. ^ a b Lo WL, Weiss A (2021-04-16). "Adapting T Cell Receptor Ligand Discrimination Capability via LAT". Frontiers in Immunology. 12: 673196. doi:10.3389/fimmu.2021.673196. PMC 8085316. PMID 33936119.
  10. ^ Shah K, Al-Haidari A, Sun J, Kazi JU (December 2021). "T cell receptor (TCR) signaling in health and disease". Signal Transduction and Targeted Therapy. 6 (1): 412. doi:10.1038/s41392-021-00823-w. PMC 8666445. PMID 34897277.
  11. ^ a b c Bartelt RR, Houtman JC (2013). "The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation". Wiley Interdisciplinary Reviews. Systems Biology and Medicine. 5 (1): 101–110. doi:10.1002/wsbm.1194. PMC 3883108. PMID 23150273.
  12. ^ Sieh M, Batzer A, Schlessinger J, Weiss A (July 1994). "GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation". Molecular and Cellular Biology. 14 (7): 4435–4442. doi:10.1128/MCB.14.7.4435. PMC 358815. PMID 7516467.
  13. ^ 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. doi:10.1084/jem.187.7.1157. PMC 2212210. PMID 9529333.
  14. ^ 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. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361. S2CID 14131281.
  15. ^ 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". The Journal of Experimental Medicine. 189 (9): 1383–1390. doi:10.1084/jem.189.9.1383. PMC 2193052. PMID 10224278.
  16. ^ a b c d e Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, et al. (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry. 41 (34): 10732–10740. doi:10.1021/bi025554o. PMID 12186560.
  17. ^ a b c d e Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A (June 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". The Biochemical Journal. 356 (Pt 2): 461–471. doi:10.1042/0264-6021:3560461. PMC 1221857. PMID 11368773.
  18. ^ 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. doi:10.1074/jbc.274.41.29323. PMID 10506192.
  19. ^ Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, et al. (June 2001). "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". The Journal of Biological Chemistry. 276 (22): 18908–18914. doi:10.1074/jbc.M101485200. PMID 11279207.
  20. ^ 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. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044.
  21. ^ 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. doi:10.1074/jbc.274.39.28050. PMID 10488157.
  22. ^ Lindholm CK, Henriksson ML, Hallberg B, Welsh M (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry. 269 (13): 3279–3288. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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