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Superactivation of integrin alphavbeta3 by low antagonist concentrations

Legler, D. F.
Ross, F. P.
Published in Journal of cell science. 2001, vol. 114, no. Pt 8, p. 1545-1553
Abstract Integrins are implicated in cell adhesion, migration and homeostasis. An important feature is their ability to adopt different affinity states that can be regulated by a variety of intra- and extracellular factors. To study affinity modulation of the integrin ectodomain by extracellular factors, we produced a soluble recombinant form of mouse integrin alphavbeta3 in a mammalian expression system and isolated it to purity. We show that the two transmembrane truncated integrin subunits stably associate to form a functional receptor, soluble recombinant alphavbeta3. The affinity of this receptor for its ligands vitronectin, fibronectin and fibrinogen can be modulated by the divalent cations magnesium, calcium and manganese. Most importantly, we found that a cyclic RGD-peptide has a biphasic effect on rsalphavbeta3and native purified alphavbeta3, with an antagonistic phase at high concentrations, and an agonistic phase at low concentrations. This integrin superactivation by low antagonist concentrations is shown in binding of sralphavbeta3 to immobilized ligands by ELISA, and in adhesion of cells that express the chimaeric integrin ligand KISS31 to immobilized rsalphavbeta3 and native purified alphavbeta3. Our results indicate that low concentrations of the ligand mimetic cyclo-RGD can result in superactivation of the extracellular domain of integrin alphavbeta3 to a comparable level as activation by manganese.
Keywords Cell Adhesion/ drug effectsCell LineDose-Response Relationship, DrugHumansModels, BiologicalOligopeptides/ administration & dosageReceptors, Vitronectin/ agonists/ antagonists & inhibitorsRecombinant Proteins/ biosynthesis/drug effects/genetics
PMID: 11282030
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LEGLER, D. F. et al. Superactivation of integrin alphavbeta3 by low antagonist concentrations. In: Journal of Cell Science, 2001, vol. 114, n° Pt 8, p. 1545-1553.

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Deposited on : 2010-08-27

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