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

Drube, Sebastian and Weber, Franziska and Göpfert, Christiane and Loschinski, Romy and Rothe, Mandy and Boelke, Franziska and Diamanti, Michaela A. and Löhn, Tobias and Ruth, Julia and Schütz, Dagmar and Häfner, Norman and Greten, Florian R. and Stumm, Ralf and Hartmann, Karin and Krämer, Oliver H. and Dudeck, Anne and Kamradt, Thomas. (2015) TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases. Oncotarget, 6 (30). pp. 28833-28850.

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Official URL: https://edoc.unibas.ch/70756/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Allergy and Immunity (Hartmann)
UniBasel Contributors:Hartmann, Karin
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 May 2020 16:37
Deposited On:22 May 2020 16:37

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