UniProt functional annotation for Q08881



	UniProt functional annotation for Q08881

UniProt code: Q08881.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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 (PubMed:12186560, PubMed:12682224, PubMed:21725281). 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 (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity). {ECO:0000250|UniProtKB:Q03526, ECO:0000269|PubMed:12186560, ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}.

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 (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). {ECO:0000250|UniProtKB:Q03526, ECO:0000269|PubMed:15308100, ECO:0000269|PubMed:15661896, ECO:0000269|PubMed:19807924}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:17060314}. Nucleus {ECO:0000250|UniProtKB:Q03526}. Note=Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation.

Tissue specificity: T-cell lines and natural killer cell lines.

Induction: Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors. {ECO:0000269|PubMed:8504851, ECO:0000269|PubMed:9701039}.

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. {ECO:0000269|PubMed:10795735}.

Ptm: 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. {ECO:0000269|PubMed:12573241, ECO:0000269|PubMed:9312162}.

Ptm: Ubiquitinated. {ECO:0000269|PubMed:20596523}.

Disease: Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A 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. {ECO:0000269|PubMed:19425169}. Note=The disease is caused by variants affecting the gene represented in this entry.

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:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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 (PubMed:12186560, PubMed:12682224, PubMed:21725281). 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 (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity). {ECO:0000250\|UniProtKB:Q03526, ECO:0000269\|PubMed:12186560, ECO:0000269\|PubMed:12682224, ECO:0000269\|PubMed:21725281}.


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 (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). {ECO:0000250\|UniProtKB:Q03526, ECO:0000269\|PubMed:15308100, ECO:0000269\|PubMed:15661896, ECO:0000269\|PubMed:19807924}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:17060314}. Nucleus {ECO:0000250\|UniProtKB:Q03526}. Note=Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation.
Tissue specificity:		T-cell lines and natural killer cell lines.
Induction:		Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors. {ECO:0000269\|PubMed:8504851, ECO:0000269\|PubMed:9701039}.
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. {ECO:0000269\|PubMed:10795735}.
Ptm:		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. {ECO:0000269\|PubMed:12573241, ECO:0000269\|PubMed:9312162}.
Ptm:		Ubiquitinated. {ECO:0000269\|PubMed:20596523}.
Disease:		Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A 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. {ECO:0000269\|PubMed:19425169}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.