ArticleeLife2019
Kinetics of cytokine receptor trafficking determine signaling and functional selectivity.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
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Who cites it
31 citing papers in PubMed, 50 citations in OpenAlex.
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- Differential Effect of Cytokines on CD4+ T-Cell Activation, Metabolism, and Susceptibility to HIV-1 Infection.Journal of immunology research · 2026Article
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- Engineering Inducible Cell Fate Transitions by Harnessing Epigenetic Silencing.bioRxiv : the preprint server for biology · 2025Article
- A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.Cell · 2025Article
- Roles of chemical species transport and transformation in the biophysics of human pathophysiology.npj biological physics and mechanics · 2025Review
- Unveiling novel insights into human IL-6 - IL-6R interaction sites through 3D computer-guided docking and systematic site mutagenesis.Scientific reports · 2024Article
- Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency.Nature communications · 2024Article
- IL-6 and diabetic kidney disease.Frontiers in immunology · 2024Review
- An engineered interleukin-11 decoy cytokine inhibits receptor signaling and proliferation in lung adenocarcinoma.Bioengineering & translational medicine · 2023Article
- Targeting IL-6 trans-signalling: past, present and future prospects.Nature reviews. Immunology · 2023Review
- Molecular and cellular factors determining the functional pleiotropy of cytokines.The FEBS journal · 2023Review
- Mechanism of receptor assembly via the pleiotropic adipokine Leptin.Nature structural & molecular biology · 2023Article
- Structural insights into the assembly of gp130 family cytokine signaling complexes.Science advances · 2023Article
- Emerging principles of cytokine pharmacology and therapeutics.Nature reviews. Drug discovery · 2023Review
- Structural insights into the assembly and activation of the IL-27 signaling complex.EMBO reports · 2022Article
- Redistribution of TNF Receptor 1 and 2 Expression on Immune Cells in Patients with Bronchial Asthma.Cells · 2022Article
- Article
- Interleukin-2 superkines by computational design.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 4 countries.
Funding
Abstract
Cytokines activate signaling via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered IL-6 variants with different affinities to gp130 to investigate how cytokine receptor binding dwell-times influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes and induced biased signaling, with changes in receptor binding dwell-times affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This leads to a graded gene expression response and differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.