Oncotarget

Research Papers:

TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases

Sebastian Drube _, Franziska Weber, Christiane Göpfert, Romy Loschinski, Mandy Rothe, Franziska Boelke, Michaela A. Diamanti, Tobias Löhn, Julia Ruth, Dagmar Schütz, Norman Häfner, Florian R. Greten, Ralf Stumm, Karin Hartmann, Oliver H. Krämer, Anne Dudeck and Thomas Kamradt

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:28833-28850. https://doi.org/10.18632/oncotarget.5008

Metrics: PDF 788 views  |   HTML 1296 views  |   ?  


Abstract

Sebastian Drube1,*, Franziska Weber1,*, Christiane Göpfert1, Romy Loschinski1, Mandy Rothe1, Franziska Boelke1, Michaela A. Diamanti2, Tobias Löhn1, Julia Ruth1, Dagmar Schütz3, Norman Häfner4, Florian R. Greten2, Ralf Stumm3, Karin Hartmann5, Oliver H. Krämer6, Anne Dudeck7, Thomas Kamradt1

1Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany

2Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany

3Institut für Pharmakologie, Universitätsklinikum Jena, Jena, Germany

4Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, Jena, Germany

5Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, Köln, Germany

6Institut für Toxikologie, Universitätsmedizin Mainz, Mainz, Germany

7Institute for Immunology, Technische Universität Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany

*These authors have contributed equally to this work

Correspondence to:

Sebastian Drube, e-mail: Sebastian.Drube@med.uni-jena.de

Keywords: mast cells, TAK1-IKK2 activation, c-Kit-Lyn-TAK1-IKK2 complex, mitogenic signaling, NF-κB-activation

Received: July 01, 2015     Accepted: August 20, 2015     Published: September 01, 2015

ABSTRACT

NF-κB activation depends on the IKK complex consisting of the catalytically active IKK1 and 2 subunits and the scaffold protein NEMO. Hitherto, IKK2 activation has always been associated with IκBα degradation, NF-κB activation, and cytokine production. In contrast, we found that in SCF-stimulated primary bone marrow-derived mast cells (BMMCs), IKK2 is alternatively activated. Mechanistically, activated TAK1 mediates the association between c-Kit and IKK2 and therefore facilitates the Lyn-dependent IKK2 activation which suffices to mediate mitogenic signaling but, surprisingly, does not result in NF-κB activation. Moreover, the c-Kit-mediated and Lyn-dependent IKK2 activation is targeted by MyD88-dependent pathways leading to enhanced IKK2 activation and therefore to potentiated effector functions. In neoplastic cells, expressing constitutively active c-Kit mutants, activated TAK1 and IKKs do also not induce NF-κB activation but mediate uncontrolled proliferation, resistance to apoptosis and enables IL-33 to mediate c-Kit-dependent signaling. Together, we identified the formation of the c-Kit-Lyn-TAK1 signalosome which mediates IKK2 activation. Unexpectedly, this IKK activation is uncoupled from the NF-κB-machinery but is critical to modulate functional cell responses in primary-, and mediates uncontrolled proliferation and survival of tumor-mast cells. Therefore, targeting TAK1 and IKKs might be a novel approach to treat c-Kit-driven diseases.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5008