A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9.
Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.
Demoulin
J B
JB
Brussels Branch, Ludwig Institute for Cancer Research, Brussels, Belgium.
Uyttenhove
C
C
Van Roost
E
E
DeLestré
B
B
Donckers
D
D
Van Snick
J
J
Renauld
J C
JC
D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D016906:Interleukin-9 / Q000494:pharmacology / Q000502:physiology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008223:Lymphoma / Q000473:pathology; D012515:Mast-Cell Sarcoma / Q000473:pathology; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000737:chemistry; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000737:chemistry; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000737:chemistry*
D000950:Antigens, Ly; D004268:DNA-Binding Proteins; C508045:IL9R protein, human; D016906:Interleukin-9; D008894:Milk Proteins; D017467:Receptors, Erythropoietin; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3