Cyclophilin B induces integrin-mediated cell adhesion by a mechanism involving CD98-dependent activation of protein kinase C-delta and p44/42 mitogen-activated protein kinases.
Initially identified as a cyclosporin-A binding protein, cyclophilin B (CyPB) is an inflammatory mediator that induces adhesion of T lymphocytes to fibronectin, by a mechanism dependent on CD147 and alpha 4 beta 1 integrins. Recent findings have suggested that another cell membrane protein, CD98, may cooperate with CD147 to regulate beta1 integrin functions. Based on these functional relationships, we examined the contribution of CD98 in the pro-adhesive activity of CyPB, by utilizing the responsive promonocyte cell line THP-1. We demonstrated that cross-linking CD98 with CD98-AHN-18 antibody mimicked the responses induced by CyPB, i.e. homotypic aggregation, integrin-mediated adhesion to fibronectin and activation of p44/42 MAPK. Consistent with previous data, immunoprecipitation confirmed the existence of a heterocomplex wherein CD147, CD98 and beta1 integrins were associated. We then demonstrated that CyPB-induced cell adhesion and p44/42 MAPK activation were dependent on the participation of phosphoinositide 3-kinase and subsequent activation of protein kinase C-delta. Finally, silencing the expression of CD98 by RNA interference potently reduced CyPB-induced cell responses, thus confirming the role of CD98 in the pro-adhesive activity of CyPB. Altogether, our results support a model whereby CyPB induces integrin-mediated adhesion via interaction with a multimolecular unit formed by the association between CD147, CD98 and beta1 integrins.
Unité de Glycobiologie Structurale et Fonctionnelle, Unité Mixte de Recherche No. 8576 du CNRS, Institut de Recherche Fédératif No. 147, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cedex, France.
Aurélie
A
Melchior
Agnès
A
Denys
Audrey
A
Deligny
Joël
J
Mazurier
Fabrice
F
Allain
D000906:Antibodies / Q000494:pharmacology; D051926:Basigin / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D021983:Cyclophilins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D027261:Fusion Regulatory Protein-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology
D000906:Antibodies; D005353:Fibronectins; D027261:Fusion Regulatory Protein-1; D019012:Integrin beta1; D016023:Integrins; D046911:Macromolecular Substances; D051926:Basigin; C081786:cyclophilin B; D019869:Phosphatidylinositol 3-Kinases; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase