Evidence map›Paper›PMID 32474443›Full record

ArticleMolecular pharmacology2020

Kinetic Analysis of the Early Signaling Steps of the Human Chemokine Receptor CXCR4.

Cristina Perpiñá-Viciano, Ali Işbilir, Aurélien Zarca, Birgit Caspar, Laura E Kilpatrick, Stephen J Hill, Martine J Smit, Martin J Lohse, Carsten Hoffmann

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
1.0field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 24 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Regulation of CXCR4 function by S1PCell communication and signaling : CCS · 2025
    Article
  8. Article
  9. The CaSignal transduction and targeted therapy · 2024
    Article
  10. Crosstalk between purinergic receptor P2YCellular and molecular life sciences : CMLS · 2024
    Article
  11. Article
  12. Article
  13. Article
  14. Platelet P2YBMC biology · 2023
    Article
  15. Review
  16. Article
  17. Advanced fluorescence microscopy reveals disruption of dynamic CXCR4 dimerization by subpocket-specific inverse agonists.Proceedings of the National Academy of Sciences of the United States of America · 2020
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 1 institution in 3 countries.

Cristina Perpiñá-VicianoInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Ali IşbilirInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Aurélien ZarcaInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Birgit CasparInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Laura E KilpatrickInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Stephen J HillInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Martine J SmitInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).ORCID 0000-0003-2713-0238
Martin J LohseInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.).
Carsten HoffmannInstitute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, University of Jena, Jena, Germany (C.P.-V., C.H.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.-V., A.I., M.J.L., C.H.); Max-Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Amsterdam Institute for Molecules Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands (A.Z., M.J.S.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, United Kingdom (B.C., L.E.K., S.J.H.); and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., L.E.K., S.J.H.) carsten.hoffmann@med.uni-jena.de.
University of Nottingham · GB

Funding

Medical Research Council MR/N020081/1
6 · The paper itself

Abstract

G protein-coupled receptors (GPCRs) are biologic switches that transduce extracellular stimuli into intracellular responses in the cell. Temporally resolving GPCR transduction pathways is key to understanding how cell signaling occurs. Here, we investigate the kinetics and dynamics of the activation and early signaling steps of the CXC chemokine receptor (CXCR) 4 in response to its natural ligands CXC chemokine ligand (CXCL) 12 and macrophage migration inhibitory factor (MIF), using Förster resonance energy transfer-based approaches. We show that CXCR4 presents a multifaceted response to CXCL12, with receptor activation (≈0.6 seconds) followed by a rearrangement in the receptor/G protein complex (≈1 seconds), a slower dimer rearrangement (≈1.7 seconds), and prolonged G protein activation (≈4 seconds). In comparison, MIF distinctly modulates every step of the transduction pathway, indicating distinct activation mechanisms and reflecting the different pharmacological properties of these two ligands. Our study also indicates that CXCR4 exhibits some degree of ligand-independent activity, a relevant feature for drug development. SIGNIFICANCE STATEMENT: The CXC chemokine ligand (CXCL) 12/CXC chemokine receptor (CXCR) 4 axis represents a well-established therapeutic target for cancer treatment. We demonstrate that CXCR4 exhibits a multifaceted response that involves dynamic receptor dimer rearrangements and that is kinetically embedded between receptor-G protein complex rearrangements and G protein activation. The alternative endogenous ligand macrophage migration inhibitory factor behaves opposite to CXCL12 in each assay studied and does not lead to G protein activation. This detailed understanding of the receptor activation may aid in the development of more specific drugs against this target.

Indexed as

Chemokine CXCL12Fluorescence Resonance Energy TransferHEK293 CellsHumansIntramolecular OxidoreductasesKineticsMacrophage Migration-Inhibitory FactorsProtein BindingProtein MultimerizationReceptors, CXCR4Signal TransductionChemokine CXCL12CXCL12 protein, humanCXCR4 protein, humanIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMIF protein, humanReceptors, CXCR4

Identifiers

PMID32474443
PMCPMC7330677
OpenAlexW3031737935

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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.