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0  structures 33  species 0  interactions 47  sequences 2  architectures

Family: LAT (PF15234)

Summary: Linker for activation of T-cells

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This is the Wikipedia entry entitled "Linker of activated T cells". More...

Linker of activated T cells Edit Wikipedia article

linker for activation of T cells
Aliases LAT, Lat, 1, pp36
External IDs MGI: 1342293 HomoloGene: 7811 GeneCards: 27040
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 16: 28.98 – 28.99 Mb Chr 7: 126.36 – 126.37 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse

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]


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]


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]


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


  1. ^ 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. 
  2. ^ a b "Entrez Gene: LAT Linker of Activated T cells". 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ a b c d e 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. 
  9. ^ a b c d e 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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

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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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Linker for activation of T-cells Provide feedback

No Pfam abstract.

Literature references

  1. Sommers CL, Samelson LE, Love PE;, Bioessays. 2004;26:61-67.: LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways. PUBMED:14696041 EPMC:14696041

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR008359

A key event in the regulation of the adaptive immune response is the binding of major histocompatibility complex (MHC)-peptide complexes to T cell antigen receptors (TCRs). The formation of such ternary complexes induces significant biochemical changes within T cells of the host animal. The first detectable response of the T cell is the rapid accumulation of numerous tyrosine-phosphorylated proteins within the cell. Increased phosphotyrosine occurs as a consequence of the activation of several different TCR- associated, hematopoietic-specific protein kinases (PTKs), thereby perturbing the balance between those enzymes that add, and those that remove, phosphates from key tyrosine residues. These initial phosphorylation events are required for the subsequent activation of the small guanosine triphosphatase (GTPase) proteins Ras and Rac, the lipid kinase P13K and PLC- gamma1. Activation of these cytoplasmic signalling proteins ultimately leads to activation of various transcription factors (NF-AT, NF-kB, and AP-1) and increased transcription from genes that have an important role in initiating T cell proliferation, such as interleukin-2 (IL-2) [PUBMED:11756537].

An unresolved question in the field has been which molecules and what sequence of events tie together the early tyrosine phosphorylation events with the activation of these downstream signalling molecules. A likely candidate for linking the proximal and distal portions of the TCR signalling pathway is a 36kDa transmembrane protein termed LAT. LAT becomes phosphorylated after TCR engagement, thereby creating binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2, Gads, Grap, 3BP2 and Shb. It also indirectly binds SOS, c-Cbl, Vav, SLP-76 and Itk.

LAT is expressed in peripheral blood lymphocytes, thymus and spleen, as well as in other blood cells, including megakaryocytes, platelets, natural killer cells and mast cells. It is excluded from the cytosol, and is found at the plasma membrane and in the perinuclear compartment. The cellular localisation of LAT seems to be extremely sensitive to alternations in the intracellular redox balance. Reduced intracellular levels of antioxidants result in the membrane displacement of LAT (a consequence of a conformational change interfering with its insertion into the membrane), abrogation of TCR-mediated signalling and, consequently, hyporesponsiveness of T lymphocytes.

The amino acid sequence of LAT contains no recognised functional domains, but, consistent with its strong tyrosine phosphorylation upon TCR stimulation, its predicted cytoplasmic tail contains 10 tyrosines, 9 of which are conserved between mouse, rat and human proteins. In addition, LAT also has 2 cysteine residues (Cys26 and Cys29 in human) that are conserved among human, rat, mouse and bovine proteins. These residues lie proximal to the inner face of the plasma membrane: Cys26 within the TM region and Cys29 located juxtamembrane. These membrane-proximal residues are thought to play a vital role in LAT function. In fact, LAT is subject to post-translational palmitoylation of these residues, which appears to be necessary to target LAT to lipid rafts in the membrane, where it can recruit key cytosolic signalling proteins to the aggregated rafts upon TCR stimulation. Raft membrane domains are envisaged as lateral assemblies of sphingolipids and cholesterol that form ordered membrane phases [PUBMED:11756537].

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Seed source: Jackhmmer:O43561
Previous IDs: none
Type: Family
Author: Eberhardt RY, Coggill P, Hetherington K
Number in seed: 12
Number in full: 47
Average length of the domain: 204.60 aa
Average identity of full alignment: 64 %
Average coverage of the sequence by the domain: 96.04 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 29.3 32.9
Noise cut-off 25.6 24.7
Model length: 240
Family (HMM) version: 3
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