The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells.
Members of the Toll/interleukin-1 receptor (TIR) family are of importance for host defense and inflammation. Here we report that the TIR-family member interleukin-33R (IL-33R) cross-activates the receptor tyrosine kinase c-Kit in human and murine mast cells. The IL-33R-induced activation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (Erk1/2), protein kinase B (PKB), and Jun NH(2)-terminal kinase 1 (JNK1) depends on c-Kit and is required to elicit optimal effector functions. Costimulation with the c-Kit ligand stem cell factor (SCF) is necessary for IL-33-induced cytokine production in primary mast cells. The structural basis for this cross-activation is the complex formation between c-Kit, IL-33R, and IL-1R accessory protein (IL-1RAcP). We found that c-Kit and IL-1RAcP interact constitutively and that IL-33R joins this complex upon ligand binding. Our findings support a model in which signals from seemingly disparate receptors are integrated for full cellular responses.
Drube
Sebastian
S
Institut für Immunologie, Universitätsklinikum Jena, Jena, Germany.
Heink
Sylvia
S
Walter
Sabine
S
Löhn
Tobias
T
Grusser
Mandy
M
Gerbaulet
Alexander
A
Berod
Luciana
L
Schons
Julia
J
Dudeck
Anne
A
Freitag
Jenny
J
Grotha
Stefan
S
Reich
Daniela
D
Rudeschko
Olga
O
Norgauer
Johannes
J
Hartmann
Karin
K
Roers
Axel
A
Kamradt
Thomas
T
D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000378:metabolism*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D018123:Receptors, Interleukin / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D016207:Cytokines; C507767:Il1rap protein, mouse; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D053577:Interleukin-1 Receptor Accessory Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D019089:Stem Cell Factor; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit; C045073:Cre recombinase; D019426:Integrases