Tec Kinases

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.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Family Members	Tec	Btk	Itk	Rlk	Bmx
Other Names	Cytoplasmic tyrosine kinase PSCTK4 Dsrc28C	ATK BPK PSCTK1 XLA Bruton’s tyrosine kinase Xid	Emt Tsk LYK PSCTK2	Txk PSCTK5	Etk PSCTK3
Molecular Weight	73 kDaa	76.2 kDa	71.8 kDa	58 kDa, 55kDa	78 kDa
Structural Data	631 aab	659 aa	620 aa	527 aa, 502 aaa	675 aa
Isoforms	Multiple splice variants	Not Known	2 Forms in mouse that differ by 6aa	2 alternate start sites	2 alternate splice variants
Species	Human Mouse Rat Dog Chimpanzee Drosophila	Human Mouse Rat Dog Chimpanzee Chicken Drosophila	Human Mouse Rat Dog Chicken Zebrafish Skate	Human Mouse Chimpanzee Dog Rat	Human Mouse Rat Dog Chicken Drosophila
Domain Organization	PH domain Btk homology domain Tec homology domain SH3 domain SH2 domain kinase domain	PH domain Btk homology domain Tec homology domain SH3 domain SH2 domain kinase domain	PH domain Btk homology domain Tec homology region SH3 domain SH2 domain kinase domain	Cysteine repeat proline rich region SH3 domain SH2 domain kinase domain	PH domain Btk homology domain SH3-like domain SH2 domain kinase domain
Phosphorylation Sites	Tyr206 (auto) Tyr519	Tyr223 (auto) Tyr551	Tyr180 (auto) Tyr511	Tyr91 (auto) Tyr420	Tyr215 (auto) Tyr223 Tyr566
Tissue Distribution	Embryonic limb Adult liver Myeloid cells B and T cells Melanocytes Overexpression of Tec I isoform is associated with cellular transformation	B cells Myeloid cells Mast cells	T cells NK cells NK-T cells Myeloid cells Mast cells Elevated in atopic dermatitis	T cells Mast cells	Granulocytes Monocytes Endothelial cells Epithelial cells Prostate cancer cell lines Breast cancer cell lines Keratinocytes Specialized epithelial cells of thymus Elevated in metastic carcinoma cell lines
Subcellular Localization	Cytoplasm, membrane-associated	Cytoplasm, moves to plasma membrane Nucleus	Cytoplasm, moves to plasma membrane Nucleus	Cytoplasm, translocates to nucleus and plasma membrane	Cytoplasm Nucleus
Binding Partners/ Associated Proteins	Vav1 Gαq Gα12 Kit Dok-1, -2 CD28 BRDG1 Sak Lyn Fyn Hck Grb10 PI3Kp85	PKC Gβγ Gαq Gα12 Hck Lyn Fyn WASp Fas Sab Sam68 EWS Cbl TFII-I Vav F-actin Syk BLNK PLCγ Caveolin IBtk	CD28 SLP-76 Vav1 WASp Grb2 Lyn Fyn Hck PI3Kp85	Fyn Hck Lyn Grb2 SLP-76	FAK Caveolin Pak1 STAT3 PTPD1 Gα12
Upstream Activators	TCR/CD3 CD28 SCF/c-Kit BCR IL-3R IL-6R ErythropoietinR PI3K Src family kinases	BCR TNFR VEGFR Integrin IL-3 IL-5 IL-6 FcεRI CD19 CD38 CD72 Collagen CXCR4 Gβγ gp130 PKC PI3K Src family kinases	TCR CD2 CD28 CXCR4 Src family kinases PI3K Peptidyl prolyl isomerase CypA	TCR CXCR4 Src family kinases	Tie-2 VEGFR-1 TNFR Integrin Src family kinases FAK Nitric oxide Gαq Gα12 Gα13
Downstream Activation	PLK-4 BRDG1 Grb10/GrblR PI3K	PLCγ1 PLCγ2 Fas TFII-I Bright	PLCγ1 CD28 LAT WASP T-bet	PLCγ1 SLP-76	FAK caveolin Pak1 STAT3 p53
Substrates	Dok-1, -2 Vav LARG CD28 Sak	WASP Gβγ Vav Caveolin PKCθ	Not Known	PLCγ1 SLP-76	FAK Caveolin
Activators	Not Known	Not Known	Not Known	Not Known	Not Known
Selective Inhibitors	Not Known	LFM-A13 (L6920)	BMS-28507 BMS-488516 BMS-509744	Not Known	Not Known
Non-Selective Inhibitors	Herbamycin A Wortmanin (W1628) LY-294002 (L9908)	Herbamycin A Wortmanin (W1628) LY-294002 (L9908)	Rosamarinic acid Cyclophilin A Herbamycin A Wortmanin (W1628) LY-294002 (L9908)	Herbamycin A	Herbamycin A Wortmanin (W1628) LY-294002 (L9908)
Selective Activators	Not Known	Not Known	Not Known	Not Known	Not Known
Physiological Function	Activates AP1 and NFAT transcription IL2-promoter	BCR driven: PLCγ1,γ2 activation PKC activation Transcription factor activation Adhesion Apoptosis B cell maturation	TCR driven: Transcription factor activation PLCγ1 activation Th2 responses Actin reorganization Adhesion Thymic selection	TCR driven: PLCγ1 activation Th1 responses Transcription activation of IFNγ promoter	Activate STAT3 Inhibit p53 anti-apoptotic Contributes to transformation Cardioprotection
Disease Relevance	Cancer	XLA (h) xid (m)	Allergies Contact hypersensitivity Asthma	Behcets syndrome-overexpressed	Wound repair Cancer

Footnotes
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.

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References

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