UniProt functional annotation for Q03526



	UniProt functional annotation for Q03526

UniProt code: Q03526.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: 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. Required for TCR- mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2- positive subset of immature gamma-delta T-cells (PubMed:23562159). Phosphorylates TBX21 at 'Tyr-525' and mediates its interaction with GATA3 (PubMed:15662016). {ECO:0000269|PubMed:15662016, ECO:0000269|PubMed:21036902, ECO:0000269|PubMed:23562159}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; Note=Binds 1 zinc ion per subunit. {ECO:0000250};

Subunit: 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). {ECO:0000250|UniProtKB:Q08881, ECO:0000269|PubMed:15662016, ECO:0000269|PubMed:19597499, ECO:0000269|PubMed:20237289}.

Subcellular location: Cytoplasm. Nucleus {ECO:0000269|PubMed:15662016}. Note=Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation. {ECO:0000250}.

Tissue specificity: 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 stage: 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.

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

Domain: 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). {ECO:0000250}.

Ptm: 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). {ECO:0000250}.

Ptm: Ubiquitinated. {ECO:0000250}.

Disruption phenotype: Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development (PubMed:8777721, PubMed:10213685, PubMed:16860760, PubMed:21036902). Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation (PubMed:21036902). Impaired TCR- mediated calcium response in gamma-delta T-cells (PubMed:23562159). Loss of Vgamma2-positive immature thymocyte-specific transcriptomic profile, although there is no change to overall transcription factor expression levels (PubMed:23562159). Not required for the generation of IL17A expressing gamma-delta T-cells (PubMed:23562159). {ECO:0000269|PubMed:10213685, ECO:0000269|PubMed:16860760, ECO:0000269|PubMed:21036902, ECO:0000269|PubMed:23562159, ECO:0000269|PubMed:8777721}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		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. Required for TCR- mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2- positive subset of immature gamma-delta T-cells (PubMed:23562159). Phosphorylates TBX21 at 'Tyr-525' and mediates its interaction with GATA3 (PubMed:15662016). {ECO:0000269\|PubMed:15662016, ECO:0000269\|PubMed:21036902, ECO:0000269\|PubMed:23562159}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; Note=Binds 1 zinc ion per subunit. {ECO:0000250};
Subunit:		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). {ECO:0000250\|UniProtKB:Q08881, ECO:0000269\|PubMed:15662016, ECO:0000269\|PubMed:19597499, ECO:0000269\|PubMed:20237289}.
Subcellular location:		Cytoplasm. Nucleus {ECO:0000269\|PubMed:15662016}. Note=Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation. {ECO:0000250}.
Tissue specificity:		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 stage:		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.
Induction:		Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.
Domain:		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). {ECO:0000250}.
Ptm:		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). {ECO:0000250}.
Ptm:		Ubiquitinated. {ECO:0000250}.
Disruption phenotype:		Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development (PubMed:8777721, PubMed:10213685, PubMed:16860760, PubMed:21036902). Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation (PubMed:21036902). Impaired TCR- mediated calcium response in gamma-delta T-cells (PubMed:23562159). Loss of Vgamma2-positive immature thymocyte-specific transcriptomic profile, although there is no change to overall transcription factor expression levels (PubMed:23562159). Not required for the generation of IL17A expressing gamma-delta T-cells (PubMed:23562159). {ECO:0000269\|PubMed:10213685, ECO:0000269\|PubMed:16860760, ECO:0000269\|PubMed:21036902, ECO:0000269\|PubMed:23562159, ECO:0000269\|PubMed:8777721}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.