Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis.
Interleukin-9 (IL-9) is a cytokine with pleiotropic effects on mast cell and T cell lines. It exerts its effects through the IL-9R complex consisting of IL-9Ralpha and the common gammac subunit. Here we report functional evidence for receptor heteromerization for efficient signal transduction, and we define minimal requirements in the two receptor subunits for IL-9R function. Tyrosine 336 of the IL-9Ralpha and the membrane-proximal segment of gammac are both crucial for signaling. The activated IL-9R complex employs the Janus kinases JAK1 and JAK3 for subsequent activation of the signal transducer and activator transcription (STAT) factors STAT-1, STAT-3, and STAT-5. This process is independent of Tyk2. We demonstrate further that the activated STAT complexes consist of STAT-1 and STAT-5 homodimers and STAT-1-STAT-3 heterodimers. Finally, we show that IL-9R signaling in a T cell line does not result in detectable mitogen-activated protein kinase activation and leads to unsustained proliferation. Nonetheless, these T cells are efficiently protected from dexamethasone-induced apoptosis. These results further define the molecular architecture of the IL-9R and its specific connections to various biologic responses.
Bauer
J H
JH
Institute for Biochemistry, Free University Berlin, 14195 Berlin, Germany.
Liu
K D
KD
You
Y
Y
Lai
S Y
SY
Goldsmith
M A
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005354:Fibrosarcoma; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D016906:Interleukin-9 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008894:Milk Proteins; D055503:Protein Multimerization; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D006377:T-Lymphocytes, Helper-Inducer; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C508045:IL9R protein, human; D007376:Interleukin-2; D016906:Interleukin-9; D046911:Macromolecular Substances; D008894:Milk Proteins; D018123:Receptors, Interleukin; 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; D003907:Dexamethasone; 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; D017871:Calcium-Calmodulin-Dependent Protein Kinases