Functional characterization of W147A: a high-affinity interleukin-11 antagonist.
IL-11 is a member of the gp130 family of cytokines, which signal via assembly of multisubunit receptor complexes containing at least one molecule of the transmembrane signaling receptor gp130. IL-11 forms a high-affinity complex, thereby inducing gp130-dependent signaling. Previous studies have identified three distinct receptor binding sites, I, II, and III, crucial for the binding of murine IL-11 (mIL-11) to both the IL-11R and gp130. In this study, we have further characterized the role of the mIL-11 site III mutant W147A. We show that W147A is a high-affinity specific antagonist of mIL-11-mediated signaling in gp130/IL-11R-transfected Ba/F3 cells. The antagonistic action of W147A is due to its ability to competitively disrupt multimeric gp130/IL-11R signaling complex formation. We also show that W147A inhibits IL-11-mediated signaling in primary human endometrial cells, thus demonstrating the potential utility of W147A in suppressing IL-11 responses in vivo.
Underhill-Day
Nicholas
N
Cancer Research UK Growth Factor Group, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. N.UnderhillDay@bham.ac.uk
McGovern
Lisa A
LA
Karpovich
Natalia
N
Mardon
Helen J
HJ
Barton
Victoria A
VA
Heath
John K
JK
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism* / Q000494:pharmacology; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000502:physiology; D053702:Receptors, Interleukin-11; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C508428:IL11RA protein, human; C494199:IL6ST protein, human; C508429:Il11ra1 protein, mouse; C494200:Il6st protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D019000:Phosphotyrosine