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Oncotarget. 2015 Oct 6;6(30):28833-50. doi: 10.18632/oncotarget.5008.

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

Author information

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.

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.

KEYWORDS:

NF-κB-activation; TAK1-IKK2 activation; c-Kit-Lyn-TAK1-IKK2 complex; mast cells; mitogenic signaling

PMID:
26353931
PMCID:
PMC4745695
DOI:
10.18632/oncotarget.5008
[Indexed for MEDLINE]
Free PMC Article

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