Identification of a gp130 cytokine receptor critical site involved in oncostatin M response

Gp130 cytokine receptor is involved in the formation of multimeric function al receptors for interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (L IF), oncostatin Rf (OSM), ciliary neurotrophic factor, and cardiotrophin-1. Cloning of the epitope recognized by an OSM-neutralizing anti-gp130 monocl onal antibody identified a portion of gp130 receptor localized in the EF lo op of the cytokine binding domain. Site-directed mutagenesis of the corresp onding region was carried out by alanine substitution of residues 186-198. To generate type 1 or type 2 OSM receptors, gp130 mutants were expressed to gether with either LIF receptor beta or OSM receptor beta. When positions V al-189/Tyr-190 and Phe-191/Val-192 were alanine-substituted, Scatchard anal yses indicated a complete abrogation of OSM binding to both type receptors. Interestingly, binding of LIF to type 1 receptor was not affected, corrobo rating the notion that in this case gp130 mostly behaves as a converter pro tein rather than a binding receptor. The present study demonstrates that po sitions 189-192 of gp130 cytokine binding domain are essential for OSM bind ing to both gp130/LIF receptor beta and gp130/OSM receptor beta heterocompl exes.