HETEROMERIZATION OF THE GAMMA(C) 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 ce ll and T cell lines. It exerts its effects through the IL-9R complex c onsisting of IL-9R alpha and the common gamma(c) subunit, Here we repo rt functional evidence for receptor heteromerization for efficient sig nal transduction, and we define minimal requirements in the two recept or subunits for IL-9R function, Tyrosine 336 of the IL-9R alpha and th e membrane-proximal segment of gamma(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 trans cription (STAT) factors STAT-I, STAT-3, and STAT-5. This process is in dependent of Tyk2. We demonstrate further that the activated STAT comp lexes consist of STAT-1 and STAT-B homodimers and STAT-1-STAT-3 hetero dimers. Finally, we show that IL-9R signaling in a T cell line does no t result in detectable mitogen-activated protein kinase activation and leads to unsustained proliferation. Nonetheless, these T cells are ef ficiently protected from dexamethasone-induced apoptosis. These result s further define the molecular architecture of the IL-SR and its speci fic connections to various biologic responses.