TAILIEUCHUNG - Báo cáo Y học: A functional role of the membrane-proximal extracellular domains of the signal transducer gp130 in heterodimerization with the leukemia inhibitory factor receptor

gp130 is the common signal transducing receptor subunit of interleukin (IL)-6-type cytokines. gp130 either homodimerizes in response to IL-6 and IL-11 or forms heterodimers with the leukemia inhibitory factor (LIF) receptor (LIFR) in response to LIF, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) or cardiotrophinlike cytokine resulting in the onset of cytoplasmic tyrosine phosphorylation cascades. The extracellular parts of both gp130 and LIFR consist of several Ig-like and fibronectin type III-like domains. The role of the membrane-distal domains of gp130 (D1, D2, D3) and LIFR in ligand binding is well established. In this study we investigated the functional. | Eur. J. Biochem. 269 2716-2726 2002 FEBS 2002 doi A functional role of the membrane-proximal extracellular domains of the signal transducer gp130 in heterodimerization with the leukemia inhibitory factor receptor Andreas Timmermann Andrea Kiister Ingo Kurth Peter C. Heinrich and Gerhard Miiller-Newen Institut fur Biochemie Rheinisch-Westfalische Technische Hochschule Aachen Germany gp130 is the common signal transducing receptor subunit of interleukin IL -6-type cytokines. gp130 either homodimerizes in response to IL-6 and IL-11 or forms heterodimers with the leukemia inhibitory factor LIF receptor LIFR in response to LIF oncostatin M OSM ciliary neurotrophic factor CNTF cardiotrophin-1 CT-1 or cardiotrophin-like cytokine resulting in the onset of cytoplasmic tyrosine phosphorylation cascades. The extracellular parts of both gp130 and LIFR consist of several Ig-like and fibronectin type III-like domains. The role of the membrane-distal domains of gp130 D1 D2 D3 and LIFR in ligand binding is well established. In this study we investigated the functional significance of the membrane-proximal domains of gp130 D4 D5 D6 in respect to heterodimerization with LIFR. Deletion of each of the membrane-proximal domains of gp130 D4 D5 and D6 leads to LIF unresponsiveness. Replacement of the gp130 domains by the corresponding domains of the related GCSF receptor either restores weak LIF responsiveness D4-GCSFR leads to constitutive activation of gp130 D5-GCSFR or results in an inactive receptor D6-GCSFR . Mutation of a specific cysteine in D5 of gp130 C458A leads to constitutive heterodimerization with the LIFR and increased sensitivity towards LIF stimulation. Based on these findings a functional model of the gp130-LIFR heterodimer is proposed that includes contacts between D5 of gp130 and the corresponding domain D7 of the LIFR and highlights the requirement for both receptor dimerization and adequate receptor orientation as a prerequisite for

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