Linker for activation of T cells explained

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. 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] 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. 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.

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.[9]

Interactions

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

Further reading

Notes and References

  1. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE . LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation . Cell . 92 . 1 . 83–92 . January 1998 . 9489702 . 10.1016/S0092-8674(00)80901-0 . 1806525 . free .
  2. Web site: Entrez Gene: LAT Linker of Activated T cells .
  3. Horejsí V . Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling . Immunology Letters . 92 . 1–2 . 43–49 . March 2004 . 15081526 . 10.1016/j.imlet.2003.10.013 .
  4. Balagopalan L, Kortum RL, Coussens NP, Barr VA, Samelson LE . 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 . 26354432 . 4646300 . 10.1074/jbc.R115.665869 . free .
  5. Lo WL, Weiss A . Adapting T Cell Receptor Ligand Discrimination Capability via LAT . Frontiers in Immunology . 12 . 673196 . 2021-04-16 . 33936119 . 8085316 . 10.3389/fimmu.2021.673196 . free .
  6. Shah K, Al-Haidari A, Sun J, Kazi JU . T cell receptor (TCR) signaling in health and disease . Signal Transduction and Targeted Therapy . 6 . 1 . 412 . December 2021 . 34897277 . 8666445 . 10.1038/s41392-021-00823-w .
  7. Bartelt RR, Houtman JC . 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 . 23150273 . 3883108 . 10.1002/wsbm.1194 .
  8. Sieh M, Batzer A, Schlessinger J, Weiss A . 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 . 7516467 . 358815 . 10.1128/MCB.14.7.4435 .
  9. Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC, Taskén K, Imboden JB, Vaage JT . 6 . 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 . 9529333 . 2212210 . 10.1084/jem.187.7.1157 .
  10. Liu SK, Fang N, Koretzky GA, McGlade CJ . 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 . 10021361 . 10.1016/S0960-9822(99)80017-7 . 14131281 . free . 1999CBio....9...67L .
  11. Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N, Takeshita T, Tsuchiya S, Konno T, Sugamura K . 6 . 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 . 10224278 . 2193052 . 10.1084/jem.189.9.1383 .
  12. Shan X, Wange RL . 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 . 10506192 . 10.1074/jbc.274.41.29323 . free .
  13. Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, Hu MC, Wange RL, Tan TH . 6 . Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling . The Journal of Biological Chemistry . 276 . 22 . 18908–18914 . June 2001 . 11279207 . 10.1074/jbc.M101485200 . free .
  14. Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A . 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 . 11368773 . 1221857 . 10.1042/0264-6021:3560461 .
  15. Zhang W, Trible RP, Samelson LE . LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation . Immunity . 9 . 2 . 239–246 . August 1998 . 9729044 . 10.1016/S1074-7613(00)80606-8 . free .
  16. Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M . 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 . 10488157 . 10.1074/jbc.274.39.28050 . free .
  17. Lindholm CK, Henriksson ML, Hallberg B, Welsh M . Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells . European Journal of Biochemistry . 269 . 13 . 3279–3288 . July 2002 . 12084069 . 10.1046/j.1432-1033.2002.03008.x . free .
  18. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB . 6 . Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav . Biochemistry . 41 . 34 . 10732–10740 . August 2002 . 12186560 . 10.1021/bi025554o .

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