DUAL ONCOSTATIN-M (OSM) RECEPTORS - CLONING AND CHARACTERIZATION OF AN ALTERNATIVE SIGNALING SUBUNIT CONFERRING OSM-SPECIFIC RECEPTOR ACTIVATION

Oncostatin M (OSM) is a cytokine whose structural and functional featu res are similar to other members of the interleukin (IL)-6 family of c ytokines (IL-6, IL-11, leukemia inhibitory factor (LIF), granulocyte c olony-stimulating factor, ciliary neurotrophic factor, and cardiotroph in-1), many of which utilize gp130 as a common receptor subunit. A bio logically active OSM receptor has been previously described that consi sts of a heterodimer of leukemia inhibitory factor receptor (LIFR) and gp130. This LIFR gp130 complex is also a functional receptor for LIF. We have cloned and characterized an alternative subunit (OSMR beta) f or an OSM receptor complex (a heterodimer of gp130 and OSMR beta) that is activated by OSM but not by LIF. The signaling capability of speci fic receptor subunit combinations was analyzed by independent assays m easuring cell proliferation or induction of acute phase protein synthe sis. Our results demonstrate that both LIF and OSM cause tyrosine phos phorylation and activation of the gp130 LIFR combination, but the gp13 0 . OSMR beta complex is activated by OSM only. OSM-induced cellular r esponses, initiated through low affinity binding to gp130, are mediate d by two heterodimeric receptor complexes that utilize alternative sig nal transducing subunits that confer different cytokine specificities to the receptor complex.