Tec kinases represent the second largest family of nonreceptor tyrosine kinases and are activated in response to cellular stimulation by antigen receptors, integrins, growth factors, cytokines and G protein-coupled receptors. The mammalian Tec family consists of five members: Tec, Btk, Itk/Emt/Tsk, Rlk/Txk and Bmx/Etk. Tec kinases are defined by a common protein domain organization including a COOH-terminal kinase domain, preceded by Src homology-2 and 3 protein interaction domains and a Tec homology domain that includes one or two proline-rich regions that interact intramolecularly or intermolecularly with SH3 domains and contribute to kinase regulation. Importantly, most Tec kinases possess an amino terminal pleckstrin homology (PH) domain that distinguishes them from all other identified tyrosine kinases. The Tec kinases' PH domains bind to phosphatidylinositol (3,4,5) trisphosphate (PIP3), and are therefore regulated by PI3 kinase and the phosphatases SHIP and PTEN. The atypical Tec kinase Rlk/Txk lacks a PH domain and instead contains a palmitoylated series of cysteines.
With some exceptions, Tec kinases are expressed primarily in cells of hematopoietic lineages. Btk is expressed in most hematopoietic cells except T cells, whereas Itk expression is limited to mast cells, T-, NK-, and NKT cells, and Rlk is restricted to T- and mast cells. In contrast, Tec is most widely expressed and is found in liver, developing embryo, brain, endothelium and melanocytes, in addition to hematopoietic cells. Bmx is expressed in granulocytes, monocytes, and in cells of epithelial and endothelial lineages.
Activation of Tec kinases requires two major steps: 1) membrane targeting, via interactions of their PH domains with PIP3 or other proteins and 2) tyrosine phosphorylation within the kinase activation loop. Protein interactions via the SH2 and SH3 domains may also be required to disrupt intramolecular interactions and to localize the kinases in signaling complexes.
Although Tec kinases are activated by many receptors, their functions are best understood downstream of lymphocyte antigen receptors. Notably, mutations affecting Btk cause the human primary immunodeficiency, X-linked agammaglobulinemia, as well as the mouse mutant x-linked immunodeficiency, xid, characterized by impaired B cell development and function. Similarly, mutations disrupting Itk or Itk and Rlk in mice cause defective T lymphocyte development and function associated with reduced antigen receptor induced proliferation, cytokine production, adhesion and migration. Btk and Itk are required for the phosphorylation and full activation of PLC-γ and downstream readouts including mobilization of calcium and activation of MAP kinases and downstream transcription factors, including NFATs, AP-1 and NFkB. Btk also interacts with and is cross-regulated by PKC-β. Additional roles for Tec kinases in T cells include regulation of the actin cytoskeleton, adhesion and migration. Upon antigen receptor activation, Rlk, Itk and Btk can translocate to the nucleus, suggesting direct effects on transcription.
In T cells, mutation of the Tec kinases neither prevents T cell development nor signaling but instead alters the efficiency or type of T cells responses. In particular, Itk-deficiency impairs TH2 responses associated with allergy and asthma, making Itk an attractive therapeutic target for such diseases. Several inhibitors of Itk have been described; data from three highly selective Itk antagonists demonstrate putative therapeutic use for allergic-induced asthma.
In other cell types Bmx/Etk and Tec participate in the regulation of Rho and serum response factor in response to Gα12. Tec is activated in response to multiple cytokine and growth factor receptors and has also been linked to the actin cytoskeleton via interactions with Vav. Bmx/Etk also participates in signaling from integrins and roles in wound healing and cardioprotection were also recently described. Bmx Etk is also required for phosphorylation of STAT-3 in cellular transformation by Src, suggesting potential therapeutic uses for Tec kinase inhibitors in cancer.
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a) Multiple isoforms exist due to alternate initiation start sites or splicing variants.
b) Isoform Tec IV noted here, Tec isoforms I-IV have been reported for both human and mouse.