TEC (gene) explained

Tyrosine-protein kinase Tec is a tyrosine kinase that in humans is encoded by the TEC gene.^{[1] [2]} Tec kinase is expressed in hematopoietic, liver, and kidney cells and plays an important role in T-helper cell processes.^[3] Tec kinase is the name-giving member of the Tec kinase family, a family of non-receptor protein-tyrosine kinases.^[4]

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.^[5]

TEC produces two protein isoforms that differ in the SH3 domain through alternative splicing. 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. 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.

Function

Functions of Tec family kinases

Tec family kinases are involved in the intracellular signaling mechanisms of cytokine receptors, lymphocyte surface antigens, heterotrimeric G-protein-coupled receptors, and integrin molecules. They are also key players in the regulation of the immune functions.

Functions of Tec kinase

Lymphoid Cells

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. Tec kinase is activated in T cells in response to CD3 engagement and TCR/CD28 stimulation. 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. It is likely Tec kinase plays a regulatory role in this signaling pathway in activated T cells, but its full function is not known.

Tec kinase also contributes to T-helper cell functions. In Th2 cells, Tec kinase is upregulated, indicating it may perform an important function in the regulation of Th2 cells. In the absence of Tec kinase, an increase in Th17 effector/memory cells is observed during a primary immune response, indicating Tec kinase may help in controlling Th17 subsets. Additionally, Th17 cells in the absence of Tec kinase produced higher levels of IL-17A, IL-17F, IL-23R, and RORγt. This indicates Tec kinase could be used as a target to enhance Th17 cell function during reinfection with pathogens.

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.^[6]

Myeloid Cells

Tec kinase plays a role in the toll-like receptor (TLR) signaling pathway of macrophages that produces pro-inflammatory cytokines TNF-α and IL-6. Btk has an important function in this pathway, as it has been observed to bind to TLR4, MyD88, and IRAK-1 signaling proteins. Tec kinase is likely involved in the same manner in macrophages, as it has a compensatory function for Btk.

Tec kinase is activated in platelets upon platelet stimulation with thrombin or collagen. Tec kinase is involved in the regulation of PLCγ2 activation, platelet aggregation, and spreading GPVI collagen receptor. Btk plays a more important role in these processes, but Tec kinase is able to compensate for loss of Btk in XLA immune-deficient patients. Patients deficient in both Btk and Tec kinase display greatly impaired phosphorylation of PLCγ2, no aggregation of platelets in response to high doses of collagen, and greatly impaired spreading of collagen.

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. Tec kinase is also expressed in primary mast cells and erythroid cells. Its function has not been identified in these cells.

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.

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. 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.

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.

TEC gene may also be associated with myelodysplastic syndrome.^[7]

Discovery

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

Interactions

TEC (gene) has been shown to interact with:

• ARHGEF12,
• CD117,^{[8] [9]}
• DOK1,^{[8] [10]}
• GNA12,^[11]
• Janus kinase 2,^{[12] [13]} and
• Suppressor of cytokine signaling 1.^[14]

Further reading

• Mano H . Tec family of protein-tyrosine kinases: an overview of their structure and function . Cytokine & Growth Factor Reviews . 10 . 3–4 . 267–80 . 2000 . 10647781 . 10.1016/S1359-6101(99)00019-2 .
• Yang WC, Collette Y, Nunès JA, Olive D . Tec kinases: a family with multiple roles in immunity . Immunity . 12 . 4 . 373–82 . April 2000 . 10795735 . 10.1016/S1074-7613(00)80189-2 . free .
• Mano H, Ishikawa F, Nishida J, Hirai H, Takaku F . A novel protein-tyrosine kinase, tec, is preferentially expressed in liver . Oncogene . 5 . 12 . 1781–6 . December 1990 . 2284097 .
• Tang B, Mano H, Yi T, Ihle JN . Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding . Molecular and Cellular Biology . 14 . 12 . 8432–7 . December 1994 . 7526158 . 359382 . 10.1128/MCB.14.12.8432 .
• Machide M, Mano H, Todokoro K . Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain . Oncogene . 11 . 4 . 619–25 . August 1995 . 7651724 .
• Mano H, Yamashita Y, Miyazato A, Miura Y, Ozawa K . Tec protein-tyrosine kinase is an effector molecule of Lyn protein-tyrosine kinase . FASEB Journal . 10 . 5 . 637–42 . April 1996 . 8621063 . 10.1096/fasebj.10.5.8621063 . free . 27064487 .
• Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP . 6 . Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases . Science . 271 . 5250 . 822–5 . February 1996 . 8629002 . 10.1126/science.271.5250.822 . 1996Sci...271..822R . 42666246 .
• Park H, Wahl MI, Afar DE, Turck CW, Rawlings DJ, Tam C, Scharenberg AM, Kinet JP, Witte ON . 6 . Regulation of Btk function by a major autophosphorylation site within the SH3 domain . Immunity . 4 . 5 . 515–25 . May 1996 . 8630736 . 10.1016/S1074-7613(00)80417-3 . free .
• Ohta Y, Haire RN, Amemiya CT, Litman RT, Träger T, Riess O, Litman GW . Human Txk: genomic organization, structure and contiguous physical linkage with the Tec gene . Oncogene . 12 . 4 . 937–42 . February 1996 . 8632917 .
• Cory GO, MacCarthy-Morrogh L, Banin S, Gout I, Brickell PM, Levinsky RJ, Kinnon C, Lovering RC . 6 . Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways . Journal of Immunology . 157 . 9 . 3791–5 . November 1996 . 10.4049/jimmunol.157.9.3791 . 8892607 . free .
• Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T . Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK . Oncogene . 14 . 19 . 2273–82 . May 1997 . 9178903 . 10.1038/sj.onc.1201071 . 7999440 .
• Laffargue M, Monnereau L, Tuech J, Ragab A, Ragab-Thomas J, Payrastre B, Raynal P, Chap H . 6 . Integrin-dependent tyrosine phoshorylation and cytoskeletal translocation of Tec in thrombin-activated platelets . Biochemical and Biophysical Research Communications . 238 . 1 . 247–51 . September 1997 . 9299487 . 10.1006/bbrc.1997.7269 .
• Kitanaka A, Mano H, Conley ME, Campana D . Expression and activation of the nonreceptor tyrosine kinase Tec in human B cells . Blood . 91 . 3 . 940–8 . February 1998 . 9446655 . 10.1182/blood.V91.3.940 . free .
• Yang WC, Ghiotto M, Barbarat B, Olive D . The role of Tec protein-tyrosine kinase in T cell signaling . The Journal of Biological Chemistry . 274 . 2 . 607–17 . January 1999 . 9872994 . 10.1074/jbc.274.2.607 . free .
• Yang WC, Olive D . Tec kinase is involved in transcriptional regulation of IL-2 and IL-4 in the CD28 pathway . European Journal of Immunology . 29 . 6 . 1842–9 . June 1999 . 10382746 . 10.1002/(SICI)1521-4141(199906)29:06<1842::AID-IMMU1842>3.0.CO;2-D . free .
• Ohya K, Kajigaya S, Kitanaka A, Yoshida K, Miyazato A, Yamashita Y, Yamanaka T, Ikeda U, Shimada K, Ozawa K, Mano H . 6 . Molecular cloning of a docking protein, BRDG1, that acts downstream of the Tec tyrosine kinase . Proceedings of the National Academy of Sciences of the United States of America . 96 . 21 . 11976–81 . October 1999 . 10518561 . 18397 . 10.1073/pnas.96.21.11976 . 1999PNAS...9611976O . free .

Notes and References

1. Sato K, Mano H, Ariyama T, Inazawa J, Yazaki Y, Hirai H . Molecular cloning and analysis of the human Tec protein-tyrosine kinase . Leukemia . 8 . 10 . 1663–72 . October 1994 . 7934162 .
2. Web site: Entrez Gene: TEC tec protein tyrosine kinase.
3. Schmidt U, Boucheron N, Unger B, Ellmeier W . The role of Tec family kinases in myeloid cells . International Archives of Allergy and Immunology . 134 . 1 . 65–78 . May 2004 . 15133303 . 10.1159/000078339 . 30963664 .
4. Boucheron N, Ellmeier W . The role of Tec family kinases in the regulation of T-helper-cell differentiation . International Reviews of Immunology . 31 . 2 . 133–54 . April 2012 . 22449074 . 10.3109/08830185.2012.664798 . 1636844 .
5. Mano. Hiroyuki. 1999-09-01. Tec family of protein-tyrosine kinases: an overview of their structure and function. Cytokine & Growth Factor Reviews. 10. 3–4. 267–280. 10.1016/S1359-6101(99)00019-2. 10647781.
6. Horwood NJ, Urbaniak AM, Danks L . Tec family kinases in inflammation and disease . International Reviews of Immunology . 31 . 2 . 87–103 . April 2012 . 22449071 . 10.3109/08830185.2012.670334 . 207475386 .
7. Web site: TEC tec protein tyrosine kinase [Homo sapiens (human)] - Gene - NCBI]. 2021-03-06. www.ncbi.nlm.nih.gov.
8. van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M . Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells . Blood . 96 . 10 . 3406–13 . November 2000 . 11071635 . 10.1182/blood.V96.10.3406 . 1765/9530 . free .
9. Tang B, Mano H, Yi T, Ihle JN . Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding . Molecular and Cellular Biology . 14 . 12 . 8432–7 . December 1994 . 7526158 . 359382 . 10.1128/MCB.14.12.8432 .
10. Liang X, Wisniewski D, Strife A, Clarkson B, Resh MD . Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling . The Journal of Biological Chemistry . 277 . 16 . 13732–8 . April 2002 . 11825908 . 10.1074/jbc.M200277200 . free .
11. Suzuki N, Nakamura S, Mano H, Kozasa T . Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF . Proceedings of the National Academy of Sciences of the United States of America . 100 . 2 . 733–8 . January 2003 . 12515866 . 141065 . 10.1073/pnas.0234057100 . 2003PNAS..100..733S . free .
12. Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T . Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK . Oncogene . 14 . 19 . 2273–82 . May 1997 . 9178903 . 10.1038/sj.onc.1201071 . 7999440 .
13. Yamashita Y, Watanabe S, Miyazato A, Ohya K, Ikeda U, Shimada K, Komatsu N, Hatake K, Miura Y, Ozawa K, Mano H . 6 . Tec and Jak2 kinases cooperate to mediate cytokine-driven activation of c-fos transcription . Blood . 91 . 5 . 1496–507 . March 1998 . 9473212 . 10.1182/blood.V91.5.1496 . free .
14. Ohya K, Kajigaya S, Yamashita Y, Miyazato A, Hatake K, Miura Y, Ikeda U, Shimada K, Ozawa K, Mano H . 6 . SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase . The Journal of Biological Chemistry . 272 . 43 . 27178–82 . October 1997 . 9341160 . 10.1074/jbc.272.43.27178 . free .