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 neurotrophic factor and cardiotrophin-1. IL-6 and IL-11 induce gp130 homodimerization whereas the others lead to the formation of heterodimers with LIFR or OSMR. Binding epitopes for IL-6 and IL-11 are located in the immunoglobulin-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, can still activate signal transducer and activator of transcription (STAT) transcription 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 activation in response to LIF and OSM. Thus, epitopes involved in gp130 homodimerization are distinct from those leading to the formation of gp130/LIFR or gp130/OSMR heterodimers. These findings may serve as the base for rational design of gp130 antagonists that specifically interfere with bioactivity of distinct IL-6-type cytokines.
Timmermann
A
A
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse 30, D-52057, Aachen, Germany.
Pflanz
S
S
Grötzinger
J
J
Küster
A
A
Kurth
I
I
Pitard
V
V
Heinrich
P C
PC
Müller-Newen
G
G
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D019556:COS Cells; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D019281:Dimerization; D000939:Epitopes / Q000032:analysis; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D017354:Point Mutation; D017433:Protein Structure, Secondary; D018121:Receptors, Cytokine / Q000737:chemistry / Q000502:physiology; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D000939:Epitopes; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D010455:Peptides; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins; D053683:Oncostatin M; D050822:Cytokine Receptor gp130