Tyrosine-protein kinase TXK

Function

Non-receptor tyrosine kinase that plays a redundant role with ITK 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 leads to the recruitment of TXK to the cell membrane, where it is phosphorylated at Tyr-420. Phosphorylation leads to TXK full activation. Also contributes to signaling from many receptors and participates in multiple downstream pathways, including regulation of the actin cytoskeleton. Like ITK, can phosphorylate PLCG1, leading to its localization in lipid rafts and activation, followed by 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. Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with PARP1 and EEF1A1. Within the complex, phosphorylates both PARP1 and EEF1A1. Also phosphorylates key sites in LCP2 leading to the up-regulation of Th1 preferred cytokine IL-2. Phosphorylates 'Tyr-201' of CTLA4 which leads to the association of PI-3 kinase with the CTLA4 receptor.

Classification

Family (Pfam)

PF07714 PK_Tyr_Ser-Thr, PF00017 SH2, PF00018 SH3_1

InterPro

Kinase-like_dom_sf, Non-receptor_tyrosine_kinases, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser-Thr/Tyr_kinase_cat_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain, Txk_SH2, TXK_SH3, Tyr_kinase_AS, Tyr_kinase_cat_dom

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 1

• 2DM0 NMR

A predicted model is available from AlphaFold.

Gene Ontology · 18

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005730 nucleolus
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0005524 ATP binding
• GO:0004715 non-membrane spanning protein tyrosine kinase activity
• GO:0002250 adaptive immune response
• GO:0006351 DNA-templated transcription
• GO:0001819 positive regulation of cytokine production
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0032729 positive regulation of type II interferon production
• GO:0060335 positive regulation of type II interferon-mediated signaling pathway
• GO:0046777 protein autophosphorylation
• GO:0006468 protein phosphorylation
• GO:0010468 regulation of gene expression
• GO:0050852 T cell receptor signaling pathway

Drugs targeting this protein · 2

• RITLECITINIB inhibitor
• RITLECITINIB TOSYLATE inhibitor

Related proteins · sequence + function similarity

• Tyrosine-protein kinase TXK 0.97
• Tyrosine-protein kinase BTK 0.93
• Tyrosine-protein kinase BTK 0.93
• Tyrosine-protein kinase BTK 0.93
• Tyrosine-protein kinase FRK 0.92
• Tyrosine-protein kinase ITK/TSK 0.91
• Tyrosine-protein kinase Tec 0.91
• Tyrosine-protein kinase ITK/TSK 0.91
• Tyrosine protein-kinase src-2 0.91
• Tyrosine-protein kinase Tec 0.91
• Tyrosine-protein kinase transforming protein Abl 0.90
• Tyrosine-protein kinase CSK 0.89

Co-cited proteins · studied together in the literature

• Tyrosine-protein kinase TXK 1 shared papers
• Cytotoxic T-lymphocyte protein 4 1 shared papers
• 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 1 shared papers
• Elongation factor 1-alpha 1 1 shared papers
• Poly [ADP-ribose] polymerase 1 1 shared papers

Literature · 10 cited papers

• Tec kinases regulate T-lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk. Immunol. Rev. · 2009
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Txk, a member of the non-receptor tyrosine kinase of the Tec family, forms a complex with poly(ADP-ribose) polymerase 1 and elongation factor 1alpha and regulates interferon-gamma gene transcription in Th1 cells. Clin. Exp. Immunol. · 2007
• Evidence of autophosphorylation in Txk: Y91 is an autophosphorylation site. Biol. Pharm. Bull. · 2002
• Txk, a member of nonreceptor tyrosine kinase of Tec family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma gene transcription. J. Immunol. · 2002
• Membrane raft-dependent regulation of phospholipase Cgamma-1 activation in T lymphocytes. Mol. Cell. Biol. · 2001
• Txk, a nonreceptor tyrosine kinase of the Tec family, is expressed in T helper type 1 cells and regulates interferon gamma production in human T lymphocytes. J. Exp. Med. · 1999
• Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4. Biochem. Biophys. Res. Commun. · 1998
• Human Txk: genomic organization, structure and contiguous physical linkage with the Tec gene. Oncogene · 1996
• TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12. Hum. Mol. Genet. · 1994