Research Papers:
TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases
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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: [email protected]
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.
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PII: 5008