Functional Interaction of CD154 Protein with α5β1 Integrin Is Totally Independent from Its Binding to αIIbβ3 Integrin and CD40 Molecules

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,...

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Bibliographic Details
Published in:The Journal of biological chemistry 2012-05, Vol.287 (22), p.18055-18066
Main Authors: El Fakhry, Youssef, Alturaihi, Haydar, Yacoub, Daniel, Liu, Lihui, Guo, Wenyan, Leveillé, Claire, Jung, Daniel, Khzam, Lara Bou, Merhi, Yahye, Wilkins, John A., Li, Hongmin, Mourad, Walid
Format: Article
Language:English
Subjects:
Base Sequence
Blotting, Western
CD154
CD40
CD40 Antigens - metabolism
CD40 Ligand - genetics
CD40 Ligand - metabolism
Cell Signaling
DNA Primers
Flow Cytometry
Humans
Immunology
Inflammation
Integrin alpha5beta1 - metabolism
Monocytes
Mutagenesis
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation
Platelet Glycoprotein GPIIb-IIIa Complex - metabolism
Protein Binding
Receptor Cross-Talk
U937 Cells
α5β1
αIIbβ3
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Summary: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. CD154, an immuno-inflammatory molecule, binds to four receptors. CD154 differentially binds its various receptors and is capable of simultaneously interacting with multiple ones, inducing synergistic responses in monocytes. The simultaneous engagement of CD154 receptors can create a cross-talk between them. Concomitant binding of CD154 to multiple receptors is greatly significant in therapies of CD154-related diseases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.333989