TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases.
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.
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Sebastian
S
Drube
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Franziska
F
Weber
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Christiane
C
Göpfert
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Romy
R
Loschinski
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Mandy
M
Rothe
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Franziska
F
Boelke
Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
Michaela A
MA
Diamanti
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Tobias
T
Löhn
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Julia
J
Ruth
Institut für Pharmakologie, Universitätsklinikum Jena, Jena, Germany.
Dagmar
D
Schütz
Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, Jena, Germany.
Norman
N
Häfner
Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, Frankfurt, Germany.
Florian R
FR
Greten
Institut für Pharmakologie, Universitätsklinikum Jena, Jena, Germany.
Ralf
R
Stumm
Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, Köln, Germany.
Karin
K
Hartmann
Institut für Toxikologie, Universitätsmedizin Mainz, Mainz, Germany.
Oliver H
OH
Krämer
Institute for Immunology, Technische Universität Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.
Anne
A
Dudeck
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Thomas
T
Kamradt
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018345:Mice, Knockout; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D061251:Primary Cell Culture; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D000067596:Interleukin-33; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D019089:Stem Cell Factor; D019061:src-Family Kinases; D000099151:MAP Kinase Kinase Kinase 7; C507780:Myd88 protein, mouse; C060902:lyn protein-tyrosine kinase; C496562:Ikbkb protein, mouse
NF-κB-activation; TAK1-IKK2 activation; c-Kit-Lyn-TAK1-IKK2 complex; mast cells; mitogenic signaling