This entry represents the SH3 domain of Tec [, ]. Tec is a cytoplasmic (or nonreceptor) tyrosine kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain []. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions []. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils [, ]. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation and phospholipase C-gamma1 activation [].
STAP1 and STAP2 are signal-transducing adaptor proteins. They contain Pleckstrin Homology (PH) and SH2 domains along with several tyrosine phosphorylation sites.STAP1 functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. It is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity []. STAP-1 has been shown to interact with STAT5 []. STAP2 is a substrate of breast tumour kinase, an Src-type non-receptor tyrosine kinase that mediates the interactions linking proteins involved in signal transduction pathways [].
Txk is a member of the Tec protein tyrosine kinase family. It plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma [, ]. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain []. This entry includes the SH2 domain of Txk.The Tec protein tyrosine kinase family includes Tec,Btk, Itk, Bmx, and Txk. They contain an NH2-terminal pleckstrin homology (PH) domain (absent in Txk), a proline-rich region, Src-homology 3 (SH3) and SH2 domains, and a COOH-terminal PTK domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homologue also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state [, ].
STAP1 is a signal-transducing adaptor protein. It is composed of a Pleckstrin Homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an orthologue of BRDG1 (also known as BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity []. STAP-1 has been shown to interact with STAT5 []. This entry represents the SH2 domain of STAP1.In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
TXK is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. TXK forms a complex with EF-1alpha and PARP1 that regulates interferon-gamma gene transcription in Th1 cells []. This entry represents the SH3 domain of TXK.
PTKs catalyse the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Itk, also known as Tsk or Emt, is a member of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Itk contains the Tec homology (TH) domain containing one proline-rich region and a zinc-binding region [, ].Itk is expressed in T-cells and mast cells, and is important in their development and differentiation []. Of the three Tec kinases expressed in T-cells, Itk plays the predominant role in T-cell receptor (TCR) signalling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signalling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4 [, ]. In addition, Itk is crucial for the development of T-helper(Th)2 effector responses [].
ITK (also known as Tsk or Emt) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation [], and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. ITK is expressed in T-cells and mast cells, and is important in their development and differentiation [, ]. Of the three Tec kinases expressed in T-cells, ITK plays the predominant role in T-cell receptor (TCR) signaling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signaling of the T-cell costimulatory receptor CD28 [], the T-cell surface receptor CD2 [], and the chemokine receptor CXCR4 []. In addition, ITK is crucial for the development of T-helper(Th)2 effector responses []. This entry represents the SH3 domain of ITK.
The Btk-type zinc finger or Btk motif (BM) is a conserved zinc-binding motif containing conserved cysteines and a histidine that is present in certain eukaryotic signalling proteins. The motif is named after Bruton's tyrosine kinase (Btk), an enzyme which is essential for B cell maturation in humans and mice [, ]. Btk is a member of the Tec family of protein tyrosine kinases (PTK). These kinases contain a conserved Tec homology (TH) domain between the N-terminal pleckstrin homology (PH) domain () and the Src homology 3 (SH3) domain (). The N-terminal of the TH domain is highly conserved and known as the Btf motif, while the C-terminal region of the TH domain contains a proline-rich region (PRR). The Btk motif contains a conserved His and three Cys residues that form a zinc finger (although these differ from known zinc finger topologies), while PRRs are commonly involved in protein-protein interactions, including interactions with G proteins [, ]. The TH domain may be of functional importance in various signalling pathways in different species []. A complete TH domain, containing both the Btk and PRR regions, has not been found outside the Tec family; however, the Btk motif on its own does occur in other proteins, usually C-terminal to a PH domain (note that although a Btk motif always occurs C-terminal to a PH domain, not all PH domains are followed by a Btk motif).The crystal structures of Btk show that the Btk-type zinc finger has a globular core, formed by a long loop which is held together by a zinc ion, and that the Btk motif is packed against the PH domain []. The zinc-binding residues are a histidine and three cysteines, which are fully conserved in the Btk motif []. Proteins known to contain a Btk-type zinc finger include:Mammalian Bruton's tyrosine kinase (Btk), a protein tyrosine kinase involved in modulation of diverse cellular processes. Mutations affecting Btk are the cause of X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice. Mammalian Tec, Bmx, and Itk proteins, which are tyrosine protein kinases of the Tec subfamily. Drosophila tyrosine-protein kinase Btk29A, which is required for the development of proper ring canals and of male genitalia and required for adult survival. Mammalian Ras GTPase-activating proteins (RasGAP), which regulate the activation of inactive GDP-bound Ras by converting GDP to GTP.
Btk (Bruton tyrosine kinase) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Btk also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions [].Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells [, ]. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation []. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis []. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans [, ]. This entry represents the SH3 domain of Btk.
