New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain.
Activation of STAT proteins by cytokines is initiated by their Src homology 2 domain-mediated association with phosphotyrosine residues from the cytoplasmic domain of a receptor. Here, we show that the C terminus of the interleukin-22 receptor (IL-22R) recruits in a tyrosine-independent manner the coiled-coil domain of STAT3. Mutation of all IL-22R cytoplasmic tyrosines did not abolish activation of STAT3, in contrast to that of STAT1 and STAT5. Coimmunoprecipitation and glutathione S-transferase pulldown experiments showed that the coiled-coil domain of STAT3 is constitutively associated with the C-terminal part of IL-22R, and a chimeric STAT3-STAT5 protein containing the coiled-coil domain of STAT3 could be activated by this tyrosine-independent mechanism. Deletion of the C-terminal part of IL-22R dramatically decreased its ability to activate STAT3 and to mediate IL-22 activity in cell lines, demonstrating that preassociation of STAT3 with this cytokine receptor, independent from the interaction between the Src homology 2 domain and phosphotyrosines, is required for its full activity.
Dumoutier
Laure
L
Ludwig Institute for Cancer Research, B-1200 Brussels.
de Meester
Carole
C
Tavernier
Jan
J
Renauld
Jean-Christophe
JC
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D016906:Interleukin-9 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000097043:Interleukin-22
D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D016906:Interleukin-9; D007378:Interleukins; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D000097043:Interleukin-22; C415369:interleukin-22 receptor