The immunoglobulin-like module of gp130 is required for signaling by interleukin-6, but not by leukemia inhibitory factor

Hammacher, A; Richardson, RT; Layton, JE; Smith, DK; Angus, LJL; Hilton, DJ; Nicola, NA; Wijdenes, J; Simpson, RJ

Author(s): Hammacher, A; Richardson, RT; Layton, JE; Smith, DK; Angus, LJL; Hilton, DJ; Nicola, NA; Wijdenes, J; Simpson, RJ;
Details: Publication Year 1998-08-28,Volume 273,Issue #35,Page 22701-22707
Journal Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type: Journal Article
Abstract: The transmembrane protein gp130 is a shared component of the receptor complexes for the interleukin-6 (IL-6)-type cytokines, which include IL-6, leukemia inhibitory factor (LIF) and oncostatin M (OSM). In addition to its role in the generation of high affinity receptors, gp130 is required for signal transduction by these cytokines. In the present study we have examined the role of the N-terminal located, extracellular immunoglobulin (Ig)-like module of gp130 in signal transduction by IL-6 and LIF. We have expressed wild-type human gp130 or three mutants in murine myeloid M1-UR21 cells that lack functional endogenous gp130 but express the IL-6 receptor (IL-GR) and the LIF receptor (LIFR). By measuring cellular responses, such as morphological changes upon differentiation, soft agar colony formation, and induction of tyrosine phosphorylation of the signal transducer and activator of transcription, STAT3, we show that signaling by IL-6, but not LIF, is significantly reduced by mutations in the Ig-like module of gp130. However, the binding of I-125-labeled IL-6 or LIF is not affected by these mutations. We also present evidence that the Ig-like module forms part of the epitope of an anti-gp130 monoclonal antibody that neutralizes the bioactivity of IL-6, but not of LIF or OSM. The data suggest that gp130-activation by IL-6 and LIF requires different regions of gp130, that the Ig-like module of gp130 may be required for IL B-induced gp130 dimerization, and that the stoichiometry of the high affinity IL-6 receptor-complex differs from those of the receptor-complexes for LIF and OSM.
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords: STIMULATING FACTOR-RECEPTOR; IL-6 RECEPTOR; HIGH-AFFINITY; MONOCLONAL-ANTIBODIES; HEXAMERIC COMPLEX; BINDING-SITES; 2 DISTINCT; TRANSDUCER; EXPRESSION; MURINE
Publisher's Version: https://doi.org/10.1074/jbc.273.35.22701
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 1998-08-28 12:00:00