Biology:Linker for activation of T cells

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] Alternative splicing results in multiple transcript variants encoding different isoforms.[2]

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.[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] 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.[4]

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.[4] 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.[5] 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.[6]

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.[7][5] 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.[7] 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.[7]

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.[1][9]

Interactions

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


References

  1. ↑ 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. ↑ 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. 
  3. ↑ "Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling". Immunology Letters 92 (1–2): 43–49. March 2004. doi:10.1016/j.imlet.2003.10.013. PMID 15081526. 
  4. ↑ 4.0 4.1 "The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters". The Journal of Biological Chemistry 290 (44): 26422–26429. October 2015. doi:10.1074/jbc.R115.665869. PMID 26354432. 
  5. ↑ 5.0 5.1 "Adapting T Cell Receptor Ligand Discrimination Capability via LAT". Frontiers in Immunology 12: 673196. 2021-04-16. doi:10.3389/fimmu.2021.673196. PMID 33936119. 
  6. ↑ "T cell receptor (TCR) signaling in health and disease". Signal Transduction and Targeted Therapy 6 (1): 412. December 2021. doi:10.1038/s41392-021-00823-w. PMID 34897277. 
  7. ↑ 7.0 7.1 7.2 "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. 2013. doi:10.1002/wsbm.1194. PMID 23150273. 
  8. ↑ "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. July 1994. doi:10.1128/MCB.14.7.4435. PMID 7516467. 
  9. ↑ "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. April 1998. doi:10.1084/jem.187.7.1157. PMID 9529333. 
  10. ↑ "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. January 1999. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361. 
  11. ↑ "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. May 1999. doi:10.1084/jem.189.9.1383. PMID 10224278. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry 41 (34): 10732–10740. August 2002. doi:10.1021/bi025554o. PMID 12186560. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "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". The Biochemical Journal 356 (Pt 2): 461–471. June 2001. doi:10.1042/0264-6021:3560461. PMID 11368773. 
  14. ↑ "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. October 1999. doi:10.1074/jbc.274.41.29323. PMID 10506192. 
  15. ↑ "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". The Journal of Biological Chemistry 276 (22): 18908–18914. June 2001. doi:10.1074/jbc.M101485200. PMID 11279207. 
  16. ↑ "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–246. August 1998. doi:10.1016/S1074-7613(00)80606-8. PMID 9729044. 
  17. ↑ "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. September 1999. doi:10.1074/jbc.274.39.28050. PMID 10488157. 
  18. ↑ "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry 269 (13): 3279–3288. July 2002. 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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