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

// Sebastian Drube 1, * , Franziska Weber 1, * , Christiane Göpfert 1 , Romy Loschinski 1 , Mandy Rothe 1 , Franziska Boelke 1 , Michaela A. Diamanti 2 , Tobias Löhn 1 , Julia Ruth 1 , Dagmar Schütz 3 , Norman Häfner 4 , Florian R. Greten 2 , Ralf Stumm 3 , Karin Hartmann 5 , Oliver H. Krämer 6 , Anne Dudeck 7 , Thomas Kamradt 1 1 Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany 2 Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany 3 Institut für Pharmakologie, Universitätsklinikum Jena, Jena, Germany 4 Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, Jena, Germany 5 Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, Köln, Germany 6 Institut für Toxikologie, Universitätsmedizin Mainz, Mainz, Germany 7 Institute 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.