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Protein

Tyrosine-protein kinase ITK/TSK

Gene

ITK

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity).By similarity3 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi121ZincBy similarity1
Metal bindingi132ZincBy similarity1
Metal bindingi133ZincBy similarity1
Metal bindingi143ZincBy similarity1
Binding sitei391ATPPROSITE-ProRule annotation1
Active sitei482Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri113 – 149Btk-typePROSITE-ProRule annotationAdd BLAST37
Nucleotide bindingi369 – 377ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processAdaptive immunity, Immunity
LigandATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-202433 Generation of second messenger molecules
R-HSA-2871809 FCERI mediated Ca+2 mobilization
SignaLinkiQ08881
SIGNORiQ08881

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase ITK/TSK (EC:2.7.10.2)
Alternative name(s):
Interleukin-2-inducible T-cell kinase
Short name:
IL-2-inducible T-cell kinase
Kinase EMT
T-cell-specific kinase
Tyrosine-protein kinase Lyk
Gene namesi
Name:ITK
Synonyms:EMT, LYK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

EuPathDBiHostDB:ENSG00000113263.12
HGNCiHGNC:6171 ITK
MIMi186973 gene
neXtProtiNX_Q08881

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

Lymphoproliferative syndrome 1 (LPFS1)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.
See also OMIM:613011
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063424335R → W in LPFS1; shows nearly undetectable mutant ITK protein consistent with severe protein instability. 1 PublicationCorresponds to variant dbSNP:rs121908191Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi288P → G: Complete loss of interaction with PPIA/CYPA. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi3702
MalaCardsiITK
MIMi613011 phenotype
OpenTargetsiENSG00000113263
Orphaneti238505 Autosomal recessive lymphoproliferative disease
PharmGKBiPA29968

Chemistry databases

ChEMBLiCHEMBL2959
DrugBankiDB06589 Pazopanib
DB02010 Staurosporine
GuidetoPHARMACOLOGYi2046

Polymorphism and mutation databases

BioMutaiITK
DMDMi585361

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000881061 – 620Tyrosine-protein kinase ITK/TSKAdd BLAST620

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei180Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei512Phosphotyrosine; by LCKCombined sources1
Modified residuei565PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated at Tyr-512 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-180 leads to the kinase activation. The autophosphorylated Tyr-180 lies within the substrate binding sequence of the SH3 domain.2 Publications
Ubiquitinated.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ08881
PaxDbiQ08881
PeptideAtlasiQ08881
PRIDEiQ08881

PTM databases

iPTMnetiQ08881
PhosphoSitePlusiQ08881

Expressioni

Tissue specificityi

T-cell lines and natural killer cell lines.

Inductioni

Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.2 Publications

Gene expression databases

BgeeiENSG00000113263
CleanExiHS_ITK
ExpressionAtlasiQ08881 baseline and differential
GenevisibleiQ08881 HS

Interactioni

Subunit structurei

Homooligomerizes; this association negatively regulates kinase activity (By similarity). Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS (By similarity). Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Interacts with TBX21 (By similarity).By similarity3 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi109907, 35 interactors
CORUMiQ08881
DIPiDIP-29974N
IntActiQ08881, 14 interactors
MINTiQ08881
STRINGi9606.ENSP00000398655

Chemistry databases

BindingDBiQ08881

Structurei

Secondary structure

1620
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi127 – 133Combined sources7
Beta strandi148 – 152Combined sources5
Beta strandi171 – 173Combined sources3
Beta strandi175 – 180Combined sources6
Beta strandi187 – 189Combined sources3
Beta strandi197 – 205Combined sources9
Beta strandi208 – 212Combined sources5
Beta strandi214 – 216Combined sources3
Beta strandi218 – 221Combined sources4
Helixi223 – 225Combined sources3
Beta strandi226 – 228Combined sources3
Helixi360 – 362Combined sources3
Beta strandi363 – 371Combined sources9
Beta strandi373 – 375Combined sources3
Beta strandi376 – 382Combined sources7
Turni383 – 385Combined sources3
Beta strandi386 – 393Combined sources8
Turni395 – 397Combined sources3
Helixi400 – 411Combined sources12
Beta strandi421 – 425Combined sources5
Beta strandi427 – 436Combined sources10
Helixi443 – 448Combined sources6
Turni449 – 452Combined sources4
Helixi456 – 475Combined sources20
Helixi485 – 487Combined sources3
Beta strandi488 – 490Combined sources3
Helixi492 – 494Combined sources3
Beta strandi496 – 498Combined sources3
Helixi503 – 506Combined sources4
Helixi510 – 513Combined sources4
Helixi522 – 524Combined sources3
Helixi527 – 532Combined sources6
Helixi537 – 552Combined sources16
Turni553 – 555Combined sources3
Turni558 – 561Combined sources4
Helixi564 – 572Combined sources9
Beta strandi581 – 583Combined sources3
Helixi585 – 594Combined sources10
Helixi599 – 601Combined sources3
Helixi605 – 617Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1SM2X-ray2.30A/B357-620[»]
1SNUX-ray2.50A/B357-620[»]
1SNXX-ray3.20A/B357-620[»]
2E6INMR-A113-169[»]
2LMJNMR-A171-231[»]
2YUQNMR-A162-239[»]
3MIYX-ray1.67A/B357-620[»]
3MJ1X-ray1.72A357-620[»]
3MJ2X-ray1.90A357-620[»]
3QGWX-ray2.10A/B357-620[»]
3QGYX-ray2.10A/B357-620[»]
3T9TX-ray1.65A354-620[»]
3V5JX-ray2.59A/B357-620[»]
3V5LX-ray1.86A/B/C/D357-620[»]
3V8TX-ray2.00A/B357-620[»]
3V8WX-ray2.27A/B357-620[»]
4HCTX-ray1.48A354-620[»]
4HCUX-ray1.43A354-620[»]
4HCVX-ray1.48A354-620[»]
4KIOX-ray2.18A/B/C/D357-620[»]
4L7SX-ray2.03A/B357-620[»]
4M0YX-ray1.70A354-620[»]
4M0ZX-ray2.00A354-620[»]
4M12X-ray2.15A354-620[»]
4M13X-ray1.85A354-620[»]
4M14X-ray1.55A354-620[»]
4M15X-ray1.52A354-620[»]
4MF0X-ray2.67A/B357-620[»]
4MF1X-ray2.11A/B357-620[»]
4PP9X-ray2.58A/B357-620[»]
4PPAX-ray2.67A/B357-620[»]
4PPBX-ray2.82A/B357-620[»]
4PPCX-ray2.95A/B357-620[»]
4PQNX-ray1.71A357-620[»]
4QD6X-ray2.45A/B357-620[»]
4RFMX-ray2.10A357-620[»]
ProteinModelPortaliQ08881
SMRiQ08881
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ08881

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 111PHPROSITE-ProRule annotationAdd BLAST108
Domaini171 – 231SH3PROSITE-ProRule annotationAdd BLAST61
Domaini239 – 338SH2PROSITE-ProRule annotationAdd BLAST100
Domaini363 – 615Protein kinasePROSITE-ProRule annotationAdd BLAST253

Domaini

The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation.1 Publication

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri113 – 149Btk-typePROSITE-ProRule annotationAdd BLAST37

Keywords - Domaini

SH2 domain, SH3 domain, Zinc-finger

Phylogenomic databases

eggNOGiKOG0197 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000119011
HOGENOMiHOG000233859
HOVERGENiHBG008761
InParanoidiQ08881
KOiK07363
OMAiRYPVCSW
OrthoDBiEOG091G0D46
PhylomeDBiQ08881
TreeFamiTF351634

Family and domain databases

CDDicd11908 SH3_ITK, 1 hit
Gene3Di2.30.29.30, 1 hit
3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR035583 ITK_SH3
IPR011009 Kinase-like_dom_sf
IPR011993 PH-like_dom_sf
IPR001849 PH_domain
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR000980 SH2
IPR036860 SH2_dom_sf
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR001562 Znf_Btk_motif
PfamiView protein in Pfam
PF00779 BTK, 1 hit
PF00169 PH, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF00017 SH2, 1 hit
PF00018 SH3_1, 1 hit
PRINTSiPR00401 SH2DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00107 BTK, 1 hit
SM00233 PH, 1 hit
SM00252 SH2, 1 hit
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF55550 SSF55550, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50003 PH_DOMAIN, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
PS50001 SH2, 1 hit
PS50002 SH3, 1 hit
PS51113 ZF_BTK, 1 hit

Sequencei

Sequence statusi: Complete.

Q08881-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNNFILLEEQ LIKKSQQKRR TSPSNFKVRF FVLTKASLAY FEDRHGKKRT
60 70 80 90 100
LKGSIELSRI KCVEIVKSDI SIPCHYKYPF QVVHDNYLLY VFAPDRESRQ
110 120 130 140 150
RWVLALKEET RNNNSLVPKY HPNFWMDGKW RCCSQLEKLA TGCAQYDPTK
160 170 180 190 200
NASKKPLPPT PEDNRRPLWE PEETVVIALY DYQTNDPQEL ALRRNEEYCL
210 220 230 240 250
LDSSEIHWWR VQDRNGHEGY VPSSYLVEKS PNNLETYEWY NKSISRDKAE
260 270 280 290 300
KLLLDTGKEG AFMVRDSRTA GTYTVSVFTK AVVSENNPCI KHYHIKETND
310 320 330 340 350
NPKRYYVAEK YVFDSIPLLI NYHQHNGGGL VTRLRYPVCF GRQKAPVTAG
360 370 380 390 400
LRYGKWVIDP SELTFVQEIG SGQFGLVHLG YWLNKDKVAI KTIREGAMSE
410 420 430 440 450
EDFIEEAEVM MKLSHPKLVQ LYGVCLEQAP ICLVFEFMEH GCLSDYLRTQ
460 470 480 490 500
RGLFAAETLL GMCLDVCEGM AYLEEACVIH RDLAARNCLV GENQVIKVSD
510 520 530 540 550
FGMTRFVLDD QYTSSTGTKF PVKWASPEVF SFSRYSSKSD VWSFGVLMWE
560 570 580 590 600
VFSEGKIPYE NRSNSEVVED ISTGFRLYKP RLASTHVYQI MNHCWKERPE
610 620
DRPAFSRLLR QLAEIAESGL
Length:620
Mass (Da):71,831
Last modified:October 1, 1994 - v1
Checksum:iDAE396BD2309319D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti171 – 172PE → GS AA sequence (PubMed:12573241).Curated2
Sequence conflicti331V → W in AAB28072 (PubMed:8364206).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04171019R → K in a metastatic melanoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_04171123P → L in a metastatic melanoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_051696193R → Q. Corresponds to variant dbSNP:rs17054374Ensembl.1
Natural variantiVAR_063424335R → W in LPFS1; shows nearly undetectable mutant ITK protein consistent with severe protein instability. 1 PublicationCorresponds to variant dbSNP:rs121908191Ensembl.1
Natural variantiVAR_041712451R → Q in a gastric adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs779372373Ensembl.1
Natural variantiVAR_041713581R → W1 PublicationCorresponds to variant dbSNP:rs34482255Ensembl.1
Natural variantiVAR_041714587V → I1 PublicationCorresponds to variant dbSNP:rs56005928Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D13720 mRNA Translation: BAA02873.1
L10717 mRNA Translation: AAA36748.1
S65186 mRNA Translation: AAB28072.2
AK312846 mRNA Translation: BAG35699.1
CH471062 Genomic DNA Translation: EAW61608.1
BC109077 mRNA Translation: AAI09078.1
BC109078 mRNA Translation: AAI09079.1
CCDSiCCDS4336.1
PIRiS33253
RefSeqiNP_005537.3, NM_005546.3
UniGeneiHs.558348

Genome annotation databases

EnsembliENST00000422843; ENSP00000398655; ENSG00000113263
GeneIDi3702
KEGGihsa:3702
UCSCiuc003lwo.2 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiITK_HUMAN
AccessioniPrimary (citable) accession number: Q08881
Secondary accession number(s): B2R752, Q32ML7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1994
Last sequence update: October 1, 1994
Last modified: March 28, 2018
This is version 195 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
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Main funding by: National Institutes of Health