Tec

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
q
12
Kit
Dok-1, -2
CD28
BRDG1
Sak
Lyn
Fyn
Hck
Grb10
PI3Kp85
PKC
Gβγ
q
12
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
12
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
q
12
13
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