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Journal of Cell Science, Vol 114, Issue 8 1545-1553, Copyright © 2001 by Company of Biologists

JOURNAL ARTICLES

Superactivation of integrin (&agr;)v(&bgr;)3 by low antagonist concentrations

DF Legler, G Wiedle, FP Ross and BA Imhof
Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. beat.imhof@medecine.unige.ch

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 (&agr;)v(&bgr;)3 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 (&agr;)v(&bgr;)3. 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 rs(&agr;)v(&bgr;)3and native purified (&agr;)v(&bgr;)3, 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 sr(&agr;)v(&bgr;)3 to immobilized ligands by ELISA, and in adhesion of cells that express the chimaeric integrin ligand KISS31 to immobilized rs(&agr;)v(&bgr;)3 and native purified (&agr;)v(&bgr;)3. Our results indicate that low concentrations of the ligand mimetic cyclo-RGD can result in superactivation of the extracellular domain of integrin (&agr;)v(&bgr;)3 to a comparable level as activation by manganese.


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© The Company of Biologists Ltd 2001