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Inhibition of Airway Smooth Muscle Adhesion and Migration by the Disintegrin Domain of ADAM-15

¹ Molecular Immunology Section, and ² Proteomics Section, Thrombosis Research Institute; and ³ Experimental Studies Unit, Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Michael F. Scully, Ph.D., Thrombosis Research Institute, Emmanuel Kaye Building, Manresea Road, London SW3 6LR, UK. E-mail: mscully{at}tri-london.ac.uk

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 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–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 ₁-integrin, without modulating signaling pathways involved in ASMC migratory responses.

Key Words: ADAM-15 • airway smooth muscle • ₁-integrin • platelet-derived growth factor

CLINICAL RELEVANCE The disintegrin domain of ADAM-15 is shown to be capable of controlling the migration of smooth muscle cells by modulating intracellular signaling. This property is likely to engender specific roles for each ADAMs protein in healthy or diseased airways.