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Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation

Oncogene volume 26, pages 6536–6545 (2007)Cite this article

Abstract

Thirty-eight-negative kinase 1 (TNK1) is a member of the ACK-family of nonreceptor tyrosine kinases and was originally cloned from CD34+/Lin-/CD38-hematopoietic stem/progenitor cells. The signaling pathways induced by TNK1 are largely unknown. Here, we report that expression and consequent activation of TNK1 enables tumor necrosis factor α (TNFα)-induced apoptosis by selectively inhibiting TNFα-induced activation of nuclear factor-κB (NF-κB). TNK1 has no effect on NF-κB DNA binding or the composition of the NF-κB complex; however, the kinase markedly prevents TNFα-induced NF-κB transactivation. TNK1 therefore acts as a novel molecular switch that can determine the properties of TNFα signaling and therefore cell death.

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References

  • Abu-Amer Y, Ross FP, McHugh KP, Livolsi A, Peyron JF, Teitelbaum SL . (1998). Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha. J Biol Chem 273: 29417–29423.

    Article  CAS  Google Scholar 

  • Beg AA, Baltimore D . (1996). An essential role for NF-kappa B in preventing TNF-alpha-induced cell death. Science 274: 782–784.

    Article  CAS  Google Scholar 

  • Boatright KM, Salvesen GS . (2003). Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725–731.

    Article  CAS  Google Scholar 

  • Campbell KJ, Rocha S, Perkins ND . (2004). Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 13: 853–865.

    Article  CAS  Google Scholar 

  • Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T et al. (1999). RANK is essential for osteoclast and lymph node development. Genes Dev 13: 2412–2424.

    Article  CAS  Google Scholar 

  • Eickhoff B, Germeroth L, Stahl C, Kohler G, Ruller S, Schlaak M et al. (2000). Trichostatin A-mediated regulation of gene expression and protein kinase activities: reprogramming tumor cells for ribotoxic stress-induced apoptosis. Biol Chem 381: 1127–1132.

    CAS  PubMed  Google Scholar 

  • Felschow DM, Civin CI, Hoehn GT . (2000). Characterization of the tyrosine kinase Tnk1 and its binding with phospholipase C-gamma1. Biochem Biophys Res Commun 273: 294–301.

    Article  CAS  Google Scholar 

  • Fuentes-Prior P, Salvesen GS . (2004). The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 384: 201–232.

    Article  CAS  Google Scholar 

  • Green DR, Kroemer G . (2004). The pathophysiology of mitochondrial cell death. Science 305: 626–629.

    Article  CAS  Google Scholar 

  • Grumont RJ, Rourke IJ, Gerondakis S . (1999). Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 13: 400–411.

    Article  CAS  Google Scholar 

  • Hayden MS, Ghosh S . (2004). Signaling to NF-kappaB. Genes Dev 18: 2195–2224.

    Article  CAS  Google Scholar 

  • Heyninck K, Beyaert R . (2005). A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions. Trends Biochem Sci 30: 1–4.

    Article  CAS  Google Scholar 

  • Hoehn GT, Stokland T, Amin S, Ramirez M, Hawkins AL, Griffin CA et al. (1996). Tnk1: a novel intracellular tyrosine kinase gene isolated from human umbilical cord blood CD34+/Lin−/CD38− stem/progenitor cells. Oncogene 12: 903–913.

    CAS  Google Scholar 

  • Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C et al. (1996). Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha. Cell 86: 787–798.

    Article  CAS  Google Scholar 

  • Karin M, Ben-Neriah Y . (2000). Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18: 621–663.

    Article  CAS  Google Scholar 

  • Karin M, Lin A . (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3: 221–227.

    Article  CAS  Google Scholar 

  • Mukhopadhyay A, Shishodia S, Suttles J, Brittingham K, Lamothe B, Nimmanapalli R et al. (2002). Ectopic expression of protein-tyrosine kinase Bcr-Abl suppresses tumor necrosis factor (TNF)-induced NF-kappa B activation and IkappaBalpha phosphorylation. Relationship with down-regulation of TNF receptors. J Biol Chem 277: 30622–30628.

    Article  CAS  Google Scholar 

  • Navakauskiene R, Treigyte G, Gineitis A, Magnusson KE . (2004). Identification of apoptotic tyrosine-phosphorylated proteins after etoposide or retinoic acid treatment. Proteomics 4: 1029–1041.

    Article  CAS  Google Scholar 

  • Neumann B, Luz A, Pfeffer K, Holzmann B . (1996). Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. J Exp Med 184: 259–264.

    Article  CAS  Google Scholar 

  • Pasparakis M, Kousteni S, Peschon J, Kollias G . (2000). Tumor necrosis factor and the p55TNF receptor are required for optimal development of the marginal sinus and for migration of follicular dendritic cell precursors into splenic follicles. Cell Immunol 201: 33–41.

    Article  CAS  Google Scholar 

  • Schmitz ML, Baeuerle PA . (1991). The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J 10: 3805–3817.

    Article  CAS  Google Scholar 

  • Schwenzer R, Siemienski K, Liptay S, Schubert G, Peters N, Scheurich P et al. (1999). The human tumor necrosis factor (TNF) receptor-associated factor 1 gene (TRAF1) is up-regulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-kappaB and c-Jun N-terminal kinase. J Biol Chem 274: 19368–19374.

    Article  CAS  Google Scholar 

  • Taghiyev AF, Guseva NV, Sturm MT, Rokhlin OW, Cohen MB . (2005). Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment. Cancer Biol Ther 4: 382–390.

    Article  CAS  Google Scholar 

  • Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB . (2003). Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem 278: 24233–24241.

    Article  CAS  Google Scholar 

  • Tulasne D, Deheuninck J, Lourenco FC, Lamballe F, Ji Z, Leroy C et al. (2004). Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage. Mol Cell Biol 24: 10328–10339.

    Article  CAS  Google Scholar 

  • Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G . (2003). Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22: 1313–1324.

    Article  CAS  Google Scholar 

  • Wajant H, Pfizenmaier K, Scheurich P . (2003). Tumor necrosis factor signaling. Cell Death Differ 10: 45–65.

    Article  CAS  Google Scholar 

  • Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C . (1999). The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev 13: 382–387.

    Article  CAS  Google Scholar 

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Acknowledgements

Work in the lab of TS and SF is supported by the DFG (Clinical Research Group 167).

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  1. N Azoitei and A Brey: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, University of Ulm, Ulm, Germany

    N Azoitei, A Brey, T Busch, G Adler & T Seufferlein

  2. Childrens Hospital, University of Ulm, Ulm, Germany

    S Fulda

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  1. N Azoitei
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  2. A Brey
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  3. T Busch
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  4. S Fulda
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  5. G Adler
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  6. T Seufferlein
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Correspondence to T Seufferlein.

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Azoitei, N., Brey, A., Busch, T. et al. Thirty-eight-negative kinase 1 (TNK1) facilitates TNFα-induced apoptosis by blocking NF-κB activation. Oncogene 26, 6536–6545 (2007). https://doi.org/10.1038/sj.onc.1210476

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