TEC (gene)

Tyrosine-protein kinase Tec is a tyrosine kinase that in humans is encoded by the TEC gene.^[5][6] Tec kinase is expressed in hematopoietic, liver, and kidney cells and plays an important role in T-helper cell processes.^[7] Tec kinase is the name-giving member of the Tec kinase family, a family of non-receptor protein-tyrosine kinases.^[8]

Structure

Tec kinase contains five protein interaction domains. The characteristic feature of Tec family kinases is a pleckstrin homology (PH) domain on the N-terminus of the molecule followed by a Tec homology (TH) domain. The TH domain of Tec kinase contains a Btk homology (BH) motif and two proline-rich (PR) regions. The other protein interaction domains of Tec kinase include Src homology (SH) domains SH2 and SH3 and a kinase domain with enzymatic activity.^[7][9]

TEC produces two protein isoforms that differ in the SH3 domain through alternative splicing.^[7][9] Type IV isoform has a full length SH3 domain and is predominately expressed in hematopoietic cells. Type III isoform has a SH3 domain that lacks the COOH-terminal 22 residues and is predominately expressed in the liver and kidney.^[9] It is likely the shortened SH3 domain of type III Tec kinase is a disabled form.

TEC resides on chromosome 4, locus 4p12 in humans. TEC is located only 1.5kb away from TXK, another member of the Tec kinase family, making it likely these two kinase genes arose through the process of gene-duplication.^[9]

Function

Functions of Tec family kinases

Tec family kinases are involved in the intracellular signaling mechanisms of

Tec kinase has low expression in naïve T cells but is upregulated upon T-cell activation, especially in the presence of TGF-ß1 and IL-6.^[8] Tec kinase is activated in T cells in response to CD3 engagement and TCR/CD28 stimulation.^[8][9] Tec kinase plays an important role in T-cell activation. Upon TCR/CD28 stimulation, Tec kinase is recruited to the cytoplasmic tail of CD28 and takes part in a signaling pathway that leads to activation of IL-2 and IL-4 cytokine promoters.^[8] It is likely Tec kinase plays a regulatory role in this signaling pathway in activated T cells, but its full function is not known.^[8]

Tec kinase also contributes to

Tec kinase is expressed in B cells and is activated upon B-cell receptor stimulation. However, there are no B-cell phenotype changes detected in Tec-deficient mice. This is likely because Tec has overlapping functions with Btk, another member of the Tec kinase family. Deletion of Btk results in a compensatory increased expression of Tec kinase, but a change in B-cell phenotype is observed, indicating Btk has a more important role in B-cell development than Tec. When both Btk and Tec are deleted, a severe B-cell deficiency is observed.^[10]

Myeloid Cells

Tec kinase plays a role in the

Tec kinase is activated in neutrophils upon neutrophil stimulation with chemoattractant fMLP. It is not clear what the function of Tec kinase is in neutrophils.^[7] Tec kinase is also expressed in primary mast cells and erythroid cells. Its function has not been identified in these cells.^[7]

Activation

Tec kinase is activated through a similar process to other members of the Tec kinase family.  Tec kinase must first be relocated to the plasma membrane, which is mediated by the interaction of its PH domain with phospholipid PIP₃ generated from PI3-K activity. A tyrosine residue within the kinase domain of Tec kinase is then phosphorylated by Src family kinases. This allows for autophosphorylation of a tyrosine residue in the Tec kinase SH3 domain, which allows the Tec kinase to be fully activated.^[7][8][9]

Clinical Significance

Rheumatoid arthritis (RA) is an autoimmune disorder that results in swollen, painful joints. Standard treatment for RA involves recombinant antibodies and receptors, but this biological therapy is costly. Inhibition of Tec family kinases may provide an alternative treatment for RA. Btk is the main target of inhibition, but because of the compensatory role of Tec kinase to Btk, an inhibition involving both Btk and Tec kinase may be needed. Blocking Tec family kinases could reduce the production of autoantibodies from B cells, limit the secretion of proinflammatory cytokines from macrophages, and inhibit mast cell degranulation.^[10] There are no known inhibitors of Tec kinase at the present. However, Tec kinase is downregulated by dephosphorylation of PIP₃ by phosphatase enzyme SHIP and by SH2-containing tyrosine phosphatase SHP-1.^[9]

Chronic myeloid leukemia (CML) is a cancer of the white blood cells in which granulocytes proliferate. Tyrosine kinase inhibitors are largely used for treatment. Dasatinib is a tyrosine kinase inhibitor that has been found to bind to Tec kinase and Btk, limiting release of histamine and proinflammatory cytokines from granulocytes. Dasatinib has also been found to inhibit T-cell effector functions through Tec family kinase inhibition, suggesting this drug could be used to suppress immune response for transplantation and T-cell autoimmune diseases.^[10]

TEC gene may also be associated with myelodysplastic syndrome.^[11]

Discovery

Tec kinase was first discovered in 1990 while researchers investigated mouse liver for novel protein-tyrosine kinase isolation.^[9][8] Expression of Tec kinase was initially found in mouse liver, kidney, spleen, and heart.

Interactions

TEC (gene) has been shown to

References