Inhibition of airway smooth muscle adhesion and migration by the disintegrin domain of ADAM-15.
Disintegrin and metalloprotease proteins (ADAMs) are membrane-anchored glycoproteins involved in cell adhesion, cell fusion, protein ecto-domain shedding, and intracellular signaling. We examined whether the disintegrin domain of ADAM-15 (named ddADAM-15) containing an Asp-Gly-Asp (RGD) integrin-binding motif could interfere with airway smooth muscle cell (ASMC) adhesion and migration. Recombinant ddADAM-15 adhered to human ASMCs with saturation kinetics, and was beta(1)-integrin dependent. ddADAM-15 inhibited the binding of fibrinogen but not of fibronectin to ASMCs. ddADAM-15 also inhibited platelet-derived growth factor (PDGF)-induced ASMC migration, and this was reversed by an anti-beta(1)-integrin antibody. PDGF induced the activation of phosphoinositol-3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK), and selective inhibitors of these kinases inhibited PDGF-induced ASMC migration. ddADAM-15 did not inhibit PDGF-induced activation of PI3K or p38, thereby excluding these kinase pathways as a mechanism by which ddADAM-15 inhibits ASMC migration. ADAM-15 mRNA and protein were expressed under basal conditions, and both gene and protein expression were inhibited by PDGF. In summary, ddADAM-15 inhibits ASMC adhesion and migration through the beta(1)-integrin, without modulating signaling pathways involved in ASMC migratory responses.
Lu
Dong
D
Molecular Immunology Section, National Heart and Lung Institute, Imperial College London, London, UK.
Xie
Shaoping
S
Sukkar
Maria B
MB
Lu
Xinjie
X
Scully
Michael F
MF
Chung
Kian Fan
KF
D051722:ADAM Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050505:Mutant Proteins / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology
D016023:Integrins; D008565:Membrane Proteins; D050505:Mutant Proteins; D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; C098660:ADAM15 protein, human