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Article Dans Une Revue Science Signaling Année : 2016

Heparan Sulfate differently controls CXCL12α and CXCL12γ mediated cell migration through differential presentation to CXCR4

Résumé

Chemokines signal cells by interacting with G protein-coupled receptors. These chemoattractant cytokines also interact with heparan sulfate (HS), which has been thought as providing positional information within tissues in such form as haptotactic gradients along which cells can migrate directionally. However, the relationships between HS and receptor binding have not been addressed. To investigate the mechanism by which HS can modulate chemokine functions we used CXCL12, a chemokine existing in different isoforms, all signaling through CXCR4 but featuring distinct HS binding domains. Using both cell associated and solubilized CXCR4, we report that although CXCL12γ binds CXCR4 with a much higher affinity than CXCL12α, it displays strongly reduced signaling and chemotactic activities. This is caused by the CXCL12γ specific C-terminal domain, which through interacting with CXCR4 sulfotyrosines, mediates high affinity but non-productive binding to CXCR4. HS can prevent this interaction, thereby functionally presenting the chemokine to its receptor and restoring its activity to a level similar to that of CXCL12α. HS had no effect on CXCL12α binding to CXCR4 nor on its biological activity, demonstrating that the polysaccharide controls CXCL12 in an isoform specific manner. HS regulation of chemokine functions thus goes well beyond a simple immobilization process and directly modulates receptor ligation and activation.
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Dates et versions

hal-01390679 , version 1 (02-11-2016)

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Bridgette Janine Connell, Rabia Sadir, Françoise Baleux, Cédric Laguri, Jean-Philippe Kleman, et al.. Heparan Sulfate differently controls CXCL12α and CXCL12γ mediated cell migration through differential presentation to CXCR4. Science Signaling, 2016, 9 (452), pp.ra107. ⟨10.1126/scisignal.aaf1839⟩. ⟨hal-01390679⟩
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