Inhibition of airway smooth muscle adhesion and migration by the disintegrin domain of ADAM-15

Am J Respir Cell Mol Biol. 2007 Oct;37(4):494-500. doi: 10.1165/rcmb.2006-0364OC. Epub 2007 Jun 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / chemistry*
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM Proteins / pharmacology*
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Integrins / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / pharmacology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutant Proteins / pharmacology
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Respiratory System / cytology*
  • Respiratory System / drug effects*
  • Respiratory System / enzymology

Substances

  • Integrins
  • Membrane Proteins
  • Mutant Proteins
  • Platelet-Derived Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • ADAM Proteins
  • ADAM15 protein, human