title: Functional interaction of CD154 protein with α5β1 integrin is totally independent from its binding to αIIbβ3 integrin and CD40 molecules.
abstract: In addition to its classical CD40 receptor, CD154 also binds to αIIbβ3, α5β1, and αMβ2 integrins. Binding of CD154 to these receptors seems to play a key role in the pathogenic processes of chronic inflammation. This investigation was aimed at analyzing the functional interaction of CD154 with CD40, αIIbβ3, and α5β1 receptors. We found that the binding affinity of CD154 for αIIbβ3 is ∼4-fold higher than for α5β1. We also describe the generation of sCD154 mutants that lost their ability to bind CD40 or αIIbβ3 and show that CD154 residues involved in its binding to CD40 or αIIbβ3 are distinct from those implicated in its interaction to α5β1, suggesting that sCD154 may bind simultaneously to different receptors. Indeed, sCD154 can bind simultaneously to CD40 and α5β1 and biologically activate human monocytic U937 cells expressing both receptors. The simultaneous engagement of CD40 and α5β1 activates the mitogen-activated protein kinases, p38, and extracellular signal-related kinases 1/2 and synergizes in the release of inflammatory mediators MMP-2 and -9, suggesting a cross-talk between these receptors.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Saint Luc, Montréal, Quebec, Canada.
authors.forename: Youssef
authors.initials: Y
authors.lastname: El Fakhry
authors.forename: Haydar
authors.initials: H
authors.lastname: Alturaihi
authors.forename: Daniel
authors.initials: D
authors.lastname: Yacoub
authors.forename: Lihui
authors.initials: L
authors.lastname: Liu
authors.forename: Wenyan
authors.initials: W
authors.lastname: Guo
authors.forename: Claire
authors.initials: C
authors.lastname: Leveillé
authors.forename: Daniel
authors.initials: D
authors.lastname: Jung
authors.forename: Lara Bou
authors.initials: LB
authors.lastname: Khzam
authors.forename: Yahye
authors.initials: Y
authors.lastname: Merhi
authors.forename: John A
authors.initials: JA
authors.lastname: Wilkins
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D016296:Mutagenesis; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D020239:Receptor Cross-Talk; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D017931:DNA Primers; D039081:Integrin alpha5beta1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D023201:CD40 Ligand; D048051:p38 Mitogen-Activated Protein Kinases