Two different epitopes of the signal transducer gp130 sequentially cooperate on IL-6-induced receptor activation

Cytokines are keg. mediators for the regulation of hemopoiesis and the coor dination of immune responses, They exert their various functions through ac tivation of specific cell surface receptors, thereby initiating intracellul ar signal transduction cascades which lead to defined cellular responses, A s the common signal-transducing receptor subunit of at least seven differen t cytokines, gp130 is an important member of the family of hemopoietic cyto kine receptors which are characterized by the presence of at least one cyto kine-binding module, Mutants of gp130 that either lack the Ig-like domain D 1 (Delta D1) or contain a distinct mutation (F191E) within the cytokine-bin ding module have been shown to be severely impaired with respect to IL-6 in duced signal transduction, After cotransfection of COS-7 cells with a combi nation of both inactive gp130 mutants, signal transduction in response to I L-6 is restored, Whereas cells transfected with Delta D1 do not bind IL-6/s IL-6R complexes, cells transfected with the F191E mutant bind IL-6/sIL-6R w ith low affinity. Combination of Delta D1 and F191E, however, leads to high -affinity ligand binding. These data suggest that two different gp130 epito pes, one on each receptor chain, sequentially cooperate in asymmetrical bin ding of IL-6/IL-6R in a tetrameric signaling complex, On the basis of our d ata, a model for the mechanism of IL-6-induced gp130 activation is proposed .