Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, Ly / biosynthesis
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Antigens, Ly / genetics
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Apoptosis / physiology*
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Base Sequence
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Cell Division / physiology
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DNA-Binding Proteins / metabolism*
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Humans
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Interleukin-9 / pharmacology
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Interleukin-9 / physiology
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Janus Kinase 1
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Janus Kinase 3
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Lymphoma / pathology
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Mast-Cell Sarcoma / pathology
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Mice
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Milk Proteins*
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Molecular Sequence Data
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Phosphorylation
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Protein Processing, Post-Translational
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Protein-Tyrosine Kinases / metabolism
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Receptors, Erythropoietin / chemistry
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Receptors, Interleukin / chemistry*
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Receptors, Interleukin / physiology
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Receptors, Interleukin-2 / chemistry
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Receptors, Interleukin-9
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Recombinant Proteins / metabolism
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Sequence Homology, Amino Acid
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Signal Transduction
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Structure-Activity Relationship
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Trans-Activators / metabolism*
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Transfection
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Tumor Cells, Cultured
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Tyrosine / chemistry*
Substances
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Antigens, Ly
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DNA-Binding Proteins
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IL9R protein, human
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Interleukin-9
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Milk Proteins
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Receptors, Erythropoietin
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Receptors, Interleukin
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Receptors, Interleukin-2
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Receptors, Interleukin-9
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Stat1 protein, mouse
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Stat3 protein, mouse
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Trans-Activators
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Tyrosine
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK3 protein, human
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Jak1 protein, mouse
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Jak3 protein, mouse
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Janus Kinase 1
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Janus Kinase 3