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O43561 (LAT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 3, 2013. Version 122. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
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Names and origin

Protein namesRecommended name:
Linker for activation of T-cells family member 1
Alternative name(s):
36 kDa phospho-tyrosine adapter protein
Short name=pp36
p36-38
Gene names
Name:LAT
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length262 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules. Ref.7

Subunit structure

When phosphorylated, interacts directly with the PIK3R1 subunit of phosphoinositide 3-kinase and the SH2 domains of GRB2, GRAP, GRAP2, PLCG1 and PLCG2. Interacts indirectly with CBL, SOS, VAV, and LCP2. Interacts with SHB, SKAP2 and CLNK By similarity. Interacts with FCGR1A. Interacts with GRB2, PLCG1 and THEMIS upon TCR activation in thymocytes By similarity. Ref.1 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Subcellular location

Cell membrane; Single-pass type III membrane protein. Note: Present in lipid rafts. Ref.1 Ref.5

Tissue specificity

Expressed in thymus, T-cells, NK cells, mast cells and, at lower levels, in spleen. Present in T-cells but not B-cells (at protein level). Ref.1 Ref.17

Post-translational modification

Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ. Phosphorylated by ITK leading to the recruitment of VAV1 to LAT-containing complexes. Ref.1 Ref.10 Ref.12 Ref.13 Ref.14

Palmitoylation of Cys-26 and Cys-29 is required for raft targeting and efficient phosphorylation. Ref.5

Miscellaneous

Engagement of killer inhibitory receptors (KIR) disrupts the interaction of PLCG1 with LAT and blocks target cell-induced activation of PLC, maybe by inducing the dephosphorylation of LAT.

Ontologies

Keywords
   Biological processAdaptive immunity
Immunity
Mast cell degranulation
   Cellular componentCell membrane
Membrane
   Coding sequence diversityAlternative splicing
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   PTMLipoprotein
Palmitate
Phosphoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processRas protein signal transduction

Inferred from mutant phenotype PubMed 12646565. Source: HGNC

T cell activation

Traceable author statement Ref.13. Source: UniProtKB

T cell receptor signaling pathway

Traceable author statement. Source: Reactome

calcium-mediated signaling

Inferred from mutant phenotype PubMed 12646565. Source: HGNC

immune response

Inferred from direct assay PubMed 15100278. Source: HGNC

integrin-mediated signaling pathway

Inferred from direct assay PubMed 15100278. Source: HGNC

mast cell degranulation

Inferred from electronic annotation. Source: UniProtKB-KW

platelet activation

Traceable author statement. Source: Reactome

regulation of T cell activation

Inferred from mutant phenotype PubMed 12646565. Source: HGNC

   Cellular_componentimmunological synapse

Inferred from direct assay PubMed 12646565. Source: HGNC

integral to membrane

Inferred from direct assay PubMed 12646565. Source: HGNC

membrane raft

Traceable author statement PubMed 14722116. Source: HGNC

signalosome

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionSH3/SH2 adaptor activity

Inferred from direct assay Ref.1. Source: HGNC

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

LCKP062392EBI-1222766,EBI-1348
PLCG1P191742EBI-1222766,EBI-79387

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform Long (identifier: O43561-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform Short (identifier: O43561-2)

The sequence of this isoform differs from the canonical sequence as follows:
     114-142: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 262262Linker for activation of T-cells family member 1
PRO_0000083325

Regions

Topological domain1 – 44Extracellular Potential
Transmembrane5 – 2723Helical; Signal-anchor for type III membrane protein; Potential
Topological domain28 – 262235Cytoplasmic Potential
Region161 – 1644Interaction with PLCG1
Region200 – 2034Interaction with GRB2, GRAP2 and PIK3R1
Region220 – 2234Interaction with GRB2, GRAP2 and PIK3R1

Amino acid modifications

Modified residue391Phosphothreonine Ref.19
Modified residue401Phosphoserine Ref.19
Modified residue411Phosphoserine Ref.19
Modified residue431Phosphoserine Ref.19
Modified residue841Phosphoserine Ref.18
Modified residue1011Phosphoserine Ref.18 Ref.19
Modified residue1061Phosphoserine Ref.19
Modified residue1101Phosphotyrosine Probable
Modified residue1561Phosphotyrosine Probable
Modified residue1611Phosphotyrosine Probable
Modified residue2001Phosphotyrosine Ref.1
Modified residue2201Phosphotyrosine Probable
Modified residue2241Phosphoserine Ref.18
Modified residue2401Phosphoserine Ref.19
Modified residue2411Phosphoserine Ref.19
Modified residue2551Phosphotyrosine Ref.19
Lipidation261S-palmitoyl cysteine Ref.5
Lipidation291S-palmitoyl cysteine Ref.5

Natural variations

Alternative sequence114 – 14229Missing in isoform Short.
VSP_004303

Experimental info

Mutagenesis261C → A: Reduces palmitoylation; abolishes localization to lipid rafts. Ref.5
Mutagenesis291C → A: Reduces palmitoylation; impairs localization to lipid rafts. Ref.5
Mutagenesis1611Y → F: Abolishes interaction with PLCG1. Ref.11
Mutagenesis2001Y → F: Abolishes interaction with GRB2 and PIK3R1; when associated with F-220. Ref.1
Mutagenesis2201Y → F: Abolishes interaction with GRB2 and PIK3R1; when associated with F-200. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform Long [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: BCD80AE7DCA64153

FASTA26227,930
        10         20         30         40         50         60 
MEEAILVPCV LGLLLLPILA MLMALCVHCH RLPGSYDSTS SDSLYPRGIQ FKRPHTVAPW 

        70         80         90        100        110        120 
PPAYPPVTSY PPLSQPDLLP IPRSPQPLGG SHRTPSSRRD SDGANSVASY ENEGASGIRG 

       130        140        150        160        170        180 
AQAGWGVWGP SWTRLTPVSL PPEPACEDAD EDEDDYHNPG YLVVLPDSTP ATSTAAPSAP 

       190        200        210        220        230        240 
ALSTPGIRDS AFSMESIDDY VNVPESGESA EASLDGSREY VNVSQELHPG AAKTEPAALS 

       250        260 
SQEAEEVEEE GAPDYENLQE LN

« Hide

Isoform Short [UniParc].

Checksum: 0832E2D2B4220BC6
Show »

FASTA23324,985

References

« Hide 'large scale' references
[1]"LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation."
Zhang W., Sloan-Lancaster J., Kitchen J., Trible R.P., Samelson L.E.
Cell 92:83-92(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT), PROTEIN SEQUENCE OF 32-47 AND 219-233, PHOSPHORYLATION AT TYR-200, MASS SPECTROMETRY, MUTAGENESIS OF TYR-200 AND TYR-220, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INTERACTION WITH PIK3R1; GRB2; GRAP AND PLCG1.
Tissue: Leukemia.
[2]"Molecular cloning of the cDNA encoding pp36, a tyrosine-phosphorylated adaptor protein selectively expressed by T cells and natural killer cells."
Weber J.R., Orstavik S., Torgersen K.M., Danbolt N.C., Berg S.F., Ryan J.C., Tasken K., Imboden J.B., Vaage J.T.
J. Exp. Med. 187:1157-1161(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT).
Tissue: Thymus.
[3]"The sequence and analysis of duplication-rich human chromosome 16."
Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. expand/collapse author list , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A.
Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
Tissue: Colon.
[5]"LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation."
Zhang W., Trible R.P., Samelson L.E.
Immunity 9:239-246(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-26 AND CYS-29, MUTAGENESIS OF CYS-26 AND CYS-29.
[6]"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."
Lindholm C.K., Gylfe E., Zhang W., Samelson L.E., Welsh M.
J. Biol. Chem. 274:28050-28057(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SHB.
[7]"A role for the adaptor protein LAT in human NK cell-mediated cytotoxicity."
Jevremovic D., Billadeau D.D., Schoon R.A., Dick C.J., Irvin B.J., Zhang W., Samelson L.E., Abraham R.T., Leibson P.J.
J. Immunol. 162:2453-2456(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NK CELLS, INTERACTION WITH PLCG1.
[8]"Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell antigen receptor-mediated signaling."
Zhang W., Trible R.P., Zhu M., Liu S.K., McGlade C.J., Samelson L.E.
J. Biol. Chem. 275:23355-23361(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GRB2; GRAP2 AND PLCG1.
[9]"The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells."
Tridandapani S., Lyden T.W., Smith J.L., Carter J.E., Coggeshall K.M., Anderson C.L.
J. Biol. Chem. 275:20480-20487(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FCGR1A.
[10]"Interaction of linker for activation of T cells with multiple adapter proteins in platelets activated by the glycoprotein VI-selective ligand, convulxin."
Asazuma N., Wilde J.I., Berlanga O., Leduc M., Leo A., Schweighoffer E., Tybulewicz V., Bon C., Liu S.K., McGlade C.J., Schraven B., Watson S.P.
J. Biol. Chem. 275:33427-33434(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, INTERACTION WITH LCP2; SKAP2; GRB2; PLCG2 AND CBL.
[11]"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."
Paz P.E., Wang S., Clarke H., Lu X., Stokoe D., Abo A.
Biochem. J. 356:461-471(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PIK3R1 AND PLCG1, MUTAGENESIS OF TYR-161.
[12]"Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation."
Baker J.E., Majeti R., Tangye S.G., Weiss A.
Mol. Cell. Biol. 21:2393-2403(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: PROBABLE DEPHOSPHORYLATION BY PTPRJ.
[13]"Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav."
Perez-Villar J.J., Whitney G.S., Sitnick M.T., Dunn R.J., Venkatesan S., O'Day K., Schieven G.L., Lin T.A., Kanner S.B.
Biochemistry 41:10732-10740(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY ITK.
[14]"The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling."
Lin J., Weiss A.
J. Cell Biol. 162:673-682(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PROBABLE DEPHOSPHORYLATION BY PTPRJ.
[15]"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry."
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C.
Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[16]"LAT: a T lymphocyte adapter protein that couples the antigen receptor to downstream signaling pathways."
Sommers C.L., Samelson L.E., Love P.E.
Bioessays 26:61-67(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION IN T-CELLS.
[17]"Transmembrane adaptor molecules: a new category of lymphoid-cell markers."
Tedoldi S., Paterson J.C., Hansmann M.-L., Natkunam Y., Rudiger T., Angelisova P., Du M.Q., Roberton H., Roncador G., Sanchez L., Pozzobon M., Masir N., Barry R., Pileri S., Mason D.Y., Marafioti T., Horejsi V.
Blood 107:213-221(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[18]"Phosphoproteome of resting human platelets."
Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A.
J. Proteome Res. 7:526-534(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-84; SER-101 AND SER-224, MASS SPECTROMETRY.
Tissue: Platelet.
[19]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-39; SER-40; SER-41; SER-43; SER-101; SER-106; SER-240; SER-241 AND TYR-255, MASS SPECTROMETRY.
Tissue: Leukemic T-cell.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		AF036906 mRNA. Translation: AAC39637.1.
AF036905 mRNA. Translation: AAC39636.1.
AJ223280 mRNA. Translation: CAA11218.1.
AC109460 Genomic DNA. No translation available.
BC011563 mRNA. Translation: AAH11563.1.
IPIIPI00012888.
IPI00218716.
RefSeqNP_001014987.1. NM_001014987.1.
NP_001014988.1. NM_001014988.1.
NP_001014989.2. NM_001014989.1.
NP_055202.1. NM_014387.3.
UniGeneHs.632179.

3D structure databases

ProteinModelPortalO43561.
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-29231N.
IntActO43561. 6 interactions.
MINTMINT-2836977.
STRING9606.ENSP00000354119.

PTM databases

PhosphoSiteO43561.

Proteomic databases

PaxDbO43561.
PRIDEO43561.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000360872; ENSP00000354119; ENSG00000213658.
ENST00000395456; ENSP00000378841; ENSG00000213658.
GeneID27040.
KEGGhsa:27040.
UCSCuc002dsb.3. human.
uc002dsd.3. human.

Organism-specific databases

CTD27040.
GeneCardsGC16P028998.
HGNCHGNC:18874. LAT.
HPACAB002223.
CAB012978.
HPA011157.
MIM602354. gene.
neXtProtNX_O43561.
PharmGKBPA38728.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG41822.
HOGENOMHOG000081810.
HOVERGENHBG018198.
KOK07362.
OMAMESGEDY.
PhylomeDBO43561.

Enzyme and pathway databases

Pathway_Interaction_DBpi3kcipathway. Class I PI3K signaling events.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
tcrjnkpathway. JNK signaling in the CD4+ TCR pathway.
ptp1bpathway. Signaling events mediated by PTP1B.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.
ReactomeREACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpressO43561.
BgeeO43561.
CleanExHS_LAT.
GenevestigatorO43561.
GermOnlineENSG00000169682. Homo sapiens.

Family and domain databases

InterProIPR008359. Linker_for_activat_Tcells_prot.
[Graphical view]
PRINTSPR01781. LATPROTEIN.
ProtoNetSearch...

Other

ChEMBLCHEMBL5779.
GenomeRNAi27040.
NextBio49608.
SOURCESearch...

Entry information

Entry nameLAT_HUMAN
AccessionPrimary (citable) accession number: O43561
Secondary accession number(s): O43919
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: June 1, 1998
Last modified: April 3, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

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