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J Biol Chem, Vol. 273, Issue 15, 9255-9260, April 10, 1998

Heteromerization of the _c Chain with the Interleukin-9 Receptor  Subunit Leads to STAT Activation and Prevention of Apoptosis

Johannes H. Bauer^§, Kathleen D. Liu^§, Yun You^§, Stephen Y. Lai^§, and Mark A. Goldsmith^§

From the  Institute for Biochemistry, Free University Berlin, 14195 Berlin, Germany and ^§ Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California 94141-9100

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-9R and the common _c 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-9R and the membrane-proximal segment of _c 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.

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