Tyrosine-protein kinase ITK/TSK

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 (By similarity). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity).

Classification

Family (Pfam)

PF00779 BTK, PF00169 PH, PF07714 PK_Tyr_Ser-Thr, PF00017 SH2, PF00018 SH3_1

InterPro

ITK_PTKc, ITK_SH3, Kinase-like_dom_sf, Non-receptor_tyrosine_kinases, PH-like_dom_sf, PH_domain, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser-Thr/Tyr_kinase_cat_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain, Tyr_kinase_AS, Tyr_kinase_cat_dom, Znf_Btk_motif

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 37

• 1SM2 X-ray 2.30A
• 1SNU X-ray 2.50A
• 1SNX X-ray 3.20A
• 2E6I NMR
• 2LMJ NMR
• 2YUQ NMR
• 3MIY X-ray 1.67A
• 3MJ1 X-ray 1.72A
• 3MJ2 X-ray 1.90A
• 3QGW X-ray 2.10A
• 3QGY X-ray 2.10A
• 3T9T X-ray 1.65A
• … and 25 more

A predicted model is available from AlphaFold.

Gene Ontology · 17

• GO:0005911 cell-cell junction
• GO:0005829 cytosol
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0005524 ATP binding
• GO:0004715 non-membrane spanning protein tyrosine kinase activity
• GO:0008270 zinc ion binding
• GO:0002250 adaptive immune response
• GO:0050853 B cell receptor signaling pathway
• GO:0006968 cellular defense response
• GO:0046629 gamma-delta T cell activation
• GO:0035556 intracellular signal transduction
• GO:0001865 NK T cell differentiation
• GO:0001819 positive regulation of cytokine production
• GO:0007165 signal transduction
• GO:0042110 T cell activation
• GO:0050852 T cell receptor signaling pathway

Disease associations

• lymphoproliferative syndrome 1 MONDO:0013081

Drugs targeting this protein · 3

• PAZOPANIB HYDROCHLORIDE inhibitor
• RITLECITINIB inhibitor
• RITLECITINIB TOSYLATE inhibitor

Related proteins · sequence + function similarity

• Tyrosine-protein kinase ITK/TSK 0.98
• Tyrosine-protein kinase Tec 0.95
• Tyrosine-protein kinase BTK 0.94
• Tyrosine-protein kinase Tec 0.94
• Tyrosine-protein kinase BTK 0.94
• Tyrosine-protein kinase BTK 0.94
• Tyrosine-protein kinase TXK 0.91
• Tyrosine-protein kinase TXK 0.90
• Tyrosine-protein kinase transforming protein Abl 0.89
• Tyrosine-protein kinase FRK 0.88
• Cytoplasmic tyrosine-protein kinase BMX 0.88
• Tyrosine-protein kinase CSK 0.88

Co-cited proteins · studied together in the literature

• Lymphocyte cytosolic protein 2 1 shared papers
• Linker for activation of T-cells family member 1 1 shared papers
• Proto-oncogene vav 1 shared papers
• Tyrosine-protein kinase Tec 1 shared papers
• Cytoplasmic tyrosine-protein kinase BMX 1 shared papers
• E3 ubiquitin-protein ligase TRIM52 1 shared papers
• Tyrosine-protein kinase BTK 1 shared papers
• G protein-coupled receptor kinase 3 1 shared papers
• Muscle, skeletal receptor tyrosine-protein kinase 1 shared papers
• Ephrin type-A receptor 1 1 shared papers
• Serine/threonine-protein kinase PAK 3 1 shared papers
• Protein kinase C gamma type 1 shared papers

Literature · 21 cited papers

• Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J. · 2011
• Development and validation of a method for profiling post-translational modification activities using protein microarrays. PLoS ONE · 2010
• Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening. BMC Immunol. · 2009
• Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
• SH2-dependent autophosphorylation within the Tec family kinase Itk. J. Mol. Biol. · 2009
• Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Invest. · 2009
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors. J. Biol. Chem. · 2006
• Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. J. Immunol. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk. Immunity · 2004
• Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Anal. Chem. · 2004
• … and 9 more in the literature graph