ArticleFrontiers in immunology2020
β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4.
Article in Frontiers in immunology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
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- CXCR4: A Promising Novel Strategy for Lung Cancer Treatment.Biomolecules · 2026Review
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- Biomechanical signaling of cytoskeleton and membrane reorganization in tumor immune chemotactic migration.Theranostics · 2026Review
- GPCR Biased Signaling in Cancer.Handbook of experimental pharmacology · 2026Review
- Deciphering the Interlinked CXCR4-Mediated Feedback Loop Among Signaling Pathways in Diabetic Wound Healing.Current diabetes reviews · 2026Review
- Dualistic Roles of High Mobility Group Box 1 in Cancer and Inflammation.Cancer medicine · 2025Review
- CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth.Nature communications · 2025Article
- High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies.Cells · 2024Review
- SNX9 family mediates βarrestin-independent GPCR endocytosis.Communications biology · 2024Article
- Pim Kinase Inhibition Disrupts CXCR4 Signalling in Megakaryocytes and Platelets by Reducing Receptor Availability at the Surface.International journal of molecular sciences · 2024Article
- Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes.Communications biology · 2024Article
- Plerixafor for pathogen-agnostic treatment in murine thigh infection and zebrafish sepsis.Clinical and translational science · 2024Article
- The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12.Nature communications · 2024Article
- The complex nature of CXCR4 mutations in WHIM syndrome.Frontiers in immunology · 2024Review
- Tumor cells express and maintain HMGB1 in the reduced isoform to enhance CXCR4-mediated migration.Frontiers in immunology · 2024Article
- Chemokine Heteromers and Their Impact on Cellular Function-A Conceptual Framework.International journal of molecular sciences · 2023Review
- The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention.Cellular & molecular immunology · 2023Review
- Proximity Labeling to Identify β-Arrestin1 Binding Partners Downstream of Ligand-Activated G Protein-Coupled Receptors.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
12 authors at 8 institutions in 3 countries.
Funding
Abstract
The chemokine receptor CXCR4 plays a fundamental role in homeostasis and pathology by orchestrating recruitment and positioning of immune cells, under the guidance of a CXCL12 gradient. The ability of chemokines to form heterocomplexes, enhancing their function, represents an additional level of regulation on their cognate receptors. In particular, the multi-faceted activity of the heterocomplex formed between CXCL12 and the alarmin HMGB1 is emerging as an unexpected player able to modulate a variety of cell responses, spanning from tissue regeneration to chronic inflammation. Nowadays, little is known on the selective signaling pathways activated when CXCR4 is triggered by the CXCL12/HMGB1 heterocomplex. In the present work, we demonstrate that this heterocomplex acts as a CXCR4 balanced agonist, activating both G protein and β-arrestins-mediated signaling pathways to sustain chemotaxis. We generated β-arrestins knock out HeLa cells by CRISPR/Cas9 technology and show that the CXCL12/HMGB1 heterocomplex-mediated actin polymerization is primarily β-arrestin1 dependent, while chemotaxis requires both β-arrestin1 and β-arrestin2. Triggering of CXCR4 with the CXCL12/HMGB1 heterocomplex leads to an unexpected receptor retention on the cell surface, which depends on β-arrestin2. In conclusion, the CXCL12/HMGB1 heterocomplex engages the β-arrestin proteins differently from CXCL12, promoting a prompt availability of CXCR4 on the cell surface, and enhancing directional cell migration. These data unveil the signaling induced by the CXCL12/HMGB1 heterocomplex in view of identifying biased CXCR4 antagonists or agonists targeting the variety of functions it exerts.
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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.