Different epitopes are required for gp130 activation by interleukin-6, oncostatin M and leukemia inhibitory factor

Gp130 is the common signal transducing receptor subunit of interleukin (IL) -6 IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neu rotrophic factor and cardiotrophin-1, IL-6 and IL-11 induce gp130 homodimer ization whereas the others lead to the formation of heterodimers,vith LIFR or OSMR. Binding epitopes for IL-6 and IL-11 are Located in the immunoglobu lin-like domain and the cytokine binding module (CBM). Here we show that a gp130 mutant lacking domain 1, although unresponsive to IL-6 and IL-11, ran stili activate signal transducer and activator of transcription (STAT) tra nscription factors in response to LIF or OSM. Moreover, point mutations in the CBM of gp130 (F191E and V252D) that severely impair signal transduction in response to IL-6 and IL-11 differentially interfere with gp130 activati on in response to LIF and OSM. Thus, epitopes involved in gp130 homodimeriz ation are distinct from those leading to the formation of gp130/LIFR or gp1 30/OSMR heterodimers, These findings may sen-e as the base for rational des ign of gp130 antagonists that specifically interfere with bioactivity of di stinct IL-6-type cytokines. (C) 2000 Federation of European Biochemical Soc ieties.