Universität zu Köln

Drube, Sebastian, Weber, Franziska, Goepfert, Christiane, Loschinski, Romy, Rothe, Mandy, Boelke, Franziska, Diamanti, Michaela A., Loehn, Tobias, Ruth, Julia, Schuetz, Dagmar, Haefner, Norman, Greten, Florian R., Stumm, Ralf, Hartmann, Karin ORCID: 0000-0002-4595-8226, Kraemer, Oliver H., Dudeck, Anne ORCID: 0000-0002-1311-9620 and Kamradt, Thomas ORCID: 0000-0001-8443-5893 (2015). TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases. Oncotarget, 6 (30). S. 28833 - 28851. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

NF-kappa B 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 I kappa B alpha degradation, NF-kappa B 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-kappa B 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-kappa B 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-kappa B-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Drube, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Goepfert, Christiane UNSPECIFIED UNSPECIFIED UNSPECIFIED Loschinski, Romy UNSPECIFIED UNSPECIFIED UNSPECIFIED Rothe, Mandy UNSPECIFIED UNSPECIFIED UNSPECIFIED Boelke, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Diamanti, Michaela A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loehn, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruth, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuetz, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Haefner, Norman UNSPECIFIED UNSPECIFIED UNSPECIFIED Greten, Florian R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stumm, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Karin UNSPECIFIED orcid.org/0000-0002-4595-8226 UNSPECIFIED Kraemer, Oliver H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dudeck, Anne UNSPECIFIED orcid.org/0000-0002-1311-9620 UNSPECIFIED Kamradt, Thomas UNSPECIFIED orcid.org/0000-0001-8443-5893 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-389982
DOI:	10.18632/oncotarget.5008
Journal or Publication Title:	Oncotarget
Volume:	6
Number:	30
Page Range:	S. 28833 - 28851
Date:	2015
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; STEM-CELL FACTOR; TRANSFORMED MAST-CELLS; FACTOR RECEPTOR/C-KIT; TYROSINE PHOSPHORYLATION; REGULATORY SUBUNIT; DENDRITIC CELLS; KINASE COMPLEX; HUMAN LEUKEMIA; MAPK KINASE Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38998