Ligand-specific utilization of the extracellular membrane-proximal region of the gp130-related signalling receptors
- Author(s)
- Hammacher, A; Wijdenes, J; Hilton, DJ; Nicola, NA; Simpson, RJ; Layton, JE;
- Journal Title
- BIOCHEMICAL JOURNAL
- Publication Type
- Journal Article
- Abstract
- The receptor gp130 is used by the interleukin-6 (IL-6)-type cytokines, which include IL-6 and leukaemia-inhibitory factor (LIF). To investigate the role of the three extracellular membrane-proximal fibronectin-type-III-like (FNIII) modules of gp130 and the related receptor for granulocyte colony-stimulating factor (G-CSFR) in cytokine signal transduction we have transfected into murine myeloid MI-UR21 cells the chimaera (GR-FNIII)gp130, which contains the membrane-proximal FNIII modules of the G-CSFR on a gp130 backbone, and its complement, the chimaera (gp130-FNIII)GR. Whereas the binding affinities of I-125-labelled IL-6 to (GR-FNIII)gp130, or of I-125-Tyr1, 3-G-CSF to (gp130-FNIII)GR, were similar to wild-type gp130 and wild-type G-CSFR, respectively, I-125-LIF failed to bind with high affinity to (GR-FNIII)gp130. In assays measuring differentiation the (gp130-FNIII)GR cells were fully responsive to G-CSF, whereas the (GR-FNIII)gp130 cells responded fully to the agonistic anti-gp130 monoclonal antibody (mAb) B-S12, but not to IL-6 or LIF. Neutralizing mAbs that recognize the membrane-proximal FNIII modules of gp130 or the G-CSFR differentially interfered with signalling by B-S12, LIF and G-CSF. The data suggest that B-S12 and G-CSF induce the correct orientation or conformation for signalling by the wild-type and chimaeric homodimeric receptors, that the membrane-proximal region of gp130 is important for the correct formation of the signalling IL-6-IL-6 receptor-gp130 complex and that this region is also involved in LIF-dependent receptor heterodimerization and signalling.
- Publisher
- PORTLAND PRESS
- Keywords
- COLONY-STIMULATING FACTOR; LEUKEMIA INHIBITORY FACTOR; IMMUNOGLOBULIN-LIKE DOMAIN; GROWTH-HORMONE RECEPTOR; INTERLEUKIN-6 FAMILY; TRUNCATED FORMS; IL-6 RECEPTOR; ALPHA-CHAIN; GP130; GRANULOCYTE
- Publisher's Version
- https://doi.org/10.1042/0264-6021:3450025
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- Refer to copyright notice on published article.
Creation Date: 2000-01-01 12:00:00