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Protein

Tyrosine-protein kinase ITK/TSK

Gene

Itk

Organism
Mus musculus (Mouse)
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. Phosphorylates TBX21 at 'Tyr-525' and mediates its interaction with GATA3 (PubMed:15662016).2 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 bindingi127ZincBy similarity1
Metal bindingi138ZincBy similarity1
Metal bindingi139ZincBy similarity1
Metal bindingi149ZincBy similarity1
Binding sitei396ATPPROSITE-ProRule annotation1
Active sitei487Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri119 – 155Btk-typePROSITE-ProRule annotationAdd BLAST37
Nucleotide bindingi374 – 382ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • activation of phospholipase C activity Source: UniProtKB
  • adaptive immune response Source: UniProtKB
  • cytokine production Source: UniProtKB
  • innate immune response Source: GO_Central
  • interferon-gamma production Source: MGI
  • interleukin-4 production Source: MGI
  • intracellular signal transduction Source: InterPro
  • NK T cell differentiation Source: MGI
  • peptidyl-tyrosine autophosphorylation Source: GO_Central
  • protein phosphorylation Source: UniProtKB
  • regulation of cell proliferation Source: GO_Central
  • T cell receptor signaling pathway Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.10.1 3474
2.7.10.2 3474
ReactomeiR-MMU-202433 Generation of second messenger molecules
R-MMU-2871809 FCERI mediated Ca+2 mobilization

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase ITK/TSK (EC:2.7.10.2)
Alternative name(s):
IL-2-inducible T-cell kinase
Kinase EMT
Kinase TLK
T-cell-specific kinase
Gene namesi
Name:Itk
Synonyms:Emt, Tlk, Tsk
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:96621 Itk

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

Disruption phenotypei

Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development. Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation.4 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000881071 – 625Tyrosine-protein kinase ITK/TSKAdd BLAST625

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei186Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei517Phosphotyrosine; by LCKBy similarity1
Modified residuei570PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated at Tyr-517 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-186 leads to the kinase activation. The autophosphorylated Tyr-186 lies within the substrate binding sequence of the SH3 domain (By similarity).By similarity
Ubiquitinated.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ03526
MaxQBiQ03526
PaxDbiQ03526
PRIDEiQ03526

PTM databases

iPTMnetiQ03526
PhosphoSitePlusiQ03526

Expressioni

Tissue specificityi

Is detected in the thymus, lymph node and very faintly in the spleen, but is not detected in the liver, lung, kidney, heart, brain, intestine or testis. Expressed in T-lymphocytes and mast cells. It may also be expressed in natural killer cells.

Developmental stagei

Is present in the fetal thymus as early as day 14 of gestation. The levels are 5- to 10-fold higher in thymocytes than in peripheral T-cells, and increase in the thymus during development from neonate to adult.

Inductioni

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

Gene expression databases

BgeeiENSMUSG00000020395
CleanExiMM_ITK
ExpressionAtlasiQ03526 baseline and differential
GenevisibleiQ03526 MM

Interactioni

Subunit structurei

Homooligomerizes; this association negatively regulates kinase activity. 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 (PubMed:15662016).By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
PLCG1P084874EBI-647969,EBI-8013886From Bos taurus.

Protein-protein interaction databases

BioGridi200840, 5 interactors
DIPiDIP-29283N
IntActiQ03526, 7 interactors
MINTiQ03526
STRINGi10090.ENSMUSP00000020664

Structurei

Secondary structure

1625
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi178 – 180Combined sources3
Beta strandi181 – 186Combined sources6
Beta strandi192 – 195Combined sources4
Beta strandi200 – 202Combined sources3
Beta strandi203 – 205Combined sources3
Beta strandi211 – 214Combined sources4
Beta strandi215 – 218Combined sources4
Beta strandi220 – 222Combined sources3
Beta strandi224 – 226Combined sources3
Beta strandi229 – 234Combined sources6
Helixi240 – 242Combined sources3
Beta strandi243 – 246Combined sources4
Beta strandi248 – 250Combined sources3
Helixi252 – 262Combined sources11
Beta strandi268 – 272Combined sources5
Turni275 – 277Combined sources3
Beta strandi279 – 285Combined sources7
Beta strandi290 – 292Combined sources3
Beta strandi294 – 302Combined sources9
Beta strandi305 – 307Combined sources3
Beta strandi310 – 313Combined sources4
Beta strandi318 – 320Combined sources3
Helixi321 – 330Combined sources10
Beta strandi335 – 337Combined sources3
Beta strandi338 – 342Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1AWJNMR-A160-236[»]
1LUINMR-A238-344[»]
1LUKNMR-A238-344[»]
1LUMNMR-A238-344[»]
1LUNNMR-A238-344[»]
2ETZNMR-A238-344[»]
2EU0NMR-A238-344[»]
2K79NMR-A177-237[»]
B238-344[»]
2K7ANMR-A177-237[»]
B238-344[»]
2RN8NMR-A177-238[»]
2RNANMR-A177-238[»]
3S9KX-ray2.35A236-344[»]
ProteinModelPortaliQ03526
SMRiQ03526
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ03526

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 117PHPROSITE-ProRule annotationAdd BLAST114
Domaini177 – 237SH3PROSITE-ProRule annotationAdd BLAST61
Domaini245 – 343SH2PROSITE-ProRule annotationAdd BLAST99
Domaini368 – 620Protein 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 (By similarity).By similarity

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 fingeri119 – 155Btk-typePROSITE-ProRule annotationAdd BLAST37

Keywords - Domaini

SH2 domain, SH3 domain, Zinc-finger

Phylogenomic databases

eggNOGiKOG0197 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000119011
HOGENOMiHOG000233859
HOVERGENiHBG008761
InParanoidiQ03526
KOiK07363
OMAiRYPVCSW
OrthoDBiEOG091G0D46
PhylomeDBiQ03526
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
PR00402 TECBTKDOMAIN
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.

Q03526-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNNFILLEEQ LIKKSQQKRR TSPSNFKVRF FVLTKASLAY FEDRHGKKRT
60 70 80 90 100
LKGSIELSRI KCVEIVKSDI SIPCHYKYPF QTLVYLQVVH DNYLLYVFAP
110 120 130 140 150
DCESRQRWVL TLKEETRNNN SLVSKYHPNF WMDGRWRCCS QLEKPAVGCA
160 170 180 190 200
PYDPSKNASK KPLPPTPEDN RRSFQEPEET LVIALYDYQT NDPQELALRC
210 220 230 240 250
DEEYYLLDSS EIHWWRVQDK NGHEGYAPSS YLVEKSPNNL ETYEWYNKSI
260 270 280 290 300
SRDKAEKLLL DTGKEGAFMV RDSRTPGTYT VSVFTKAIIS ENPCIKHYHI
310 320 330 340 350
KETNDSPKRY YVAEKYVFDS IPLLIQYHQY NGGGLVTRLR YPVCSWRQKA
360 370 380 390 400
PVTAGLRYGK WVIQPSELTF VQEIGSGQFG LVHLGYWLNK DKVAIKTIQE
410 420 430 440 450
GAMSEEDFIE EAEVMMKLSH PKLVQLYGVC LEQAPICLVF EFMEHGCLSD
460 470 480 490 500
YLRSQRGLFA AETLLGMCLD VCEGMAYLEK ACVIHRDLAA RNCLVGENQV
510 520 530 540 550
IKVSDFGMTR FVLDDQYTSS TGTKFPVKWA SPEVFSFSRY SSKSDVWSFG
560 570 580 590 600
VLMWEVFSEG KIPYENRSNS EVVEDISTGF RLYKPRLASC HVYQIMNHCW
610 620
KEKPEDRPPF SQLLSQLAEI AEAGL
Length:625
Mass (Da):72,292
Last modified:February 1, 1995 - v1
Checksum:iF7A4A18A8A1AADDC
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti82 – 87Missing (PubMed:8421704).Curated6
Sequence conflicti82 – 87Missing (PubMed:8476425).Curated6
Sequence conflicti82 – 87Missing (Ref. 4) Curated6
Sequence conflicti535F → S in L10628 (PubMed:8476425).Curated1
Sequence conflicti540Y → C in L10628 (PubMed:8476425).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L00619 mRNA Translation: AAA39337.1
L05631 mRNA Translation: AAA40518.1
L10628 mRNA No translation available.
D14042 mRNA Translation: BAA03129.1
CCDSiCCDS70169.1
PIRiA43030
RefSeqiNP_001268894.1, NM_001281965.1
NP_001268895.1, NM_001281966.1
NP_001268897.1, NM_001281968.1
NP_034713.2, NM_010583.3
UniGeneiMm.339927

Genome annotation databases

EnsembliENSMUST00000109237; ENSMUSP00000104860; ENSMUSG00000020395
GeneIDi16428
KEGGimmu:16428
UCSCiuc011xtn.2 mouse

Similar proteinsi

Entry informationi

Entry nameiITK_MOUSE
AccessioniPrimary (citable) accession number: Q03526
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: May 23, 2018
This is version 187 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families

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