title: The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3.
abstract: The integrins alpha(v)beta(1), alpha(v)beta(5), alpha(v)beta(6) and alpha(v)beta(8) have all recently been shown to interact with the RGD motif of the latency-associated peptide (LAPbeta(1)) of transforming growth factor beta(1) (TGFbeta(1)), with binding to alpha(v)beta(6) and alpha(v)beta(8) leading to TGFbeta(1) activation. Previously it has been suggested that the remaining alpha(v) integrin, alpha(v)beta(3,) does not interact with LAPbeta(1). However, here we show clearly that alpha(v)beta(3) does indeed interact with the LAPbeta(1) RGD motif. This interaction is similar to other alpha(v)beta(3) ligands in terms of the cations required for adhesion, the concentrations of LAPbeta(1) required for binding and the ability of a small-molecule inhibitor of alpha(v)beta(3), SB223245, to block the interaction. Using glutathione S-transferase fusion proteins we have mapped a minimal integrin-binding loop in LAPbeta(1) and then used this approach to probe the integrin-binding properties of the equivalent loops in LAPbeta(2) and LAPbeta(3). We show that the RGD motif of LAPbeta(3) also interacts with alpha(v)beta(3), in addition to alpha(v)beta(6), alpha(v)beta(1) and alpha(v)beta(5), whereas the corresponding loop in LAPbeta(2) does not interact with these integrins. These observations therefore correct a previously reported inaccuracy in the literature. Furthermore, they are important as they link alpha(v)beta(3) and TGFbeta, which may have implications in cancer and a number of inflammatory and fibrotic diseases where expression of both proteins has been documented.
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001570:Benzodiazepinones / Q000378:metabolism; D001665:Binding Sites; D002448:Cell Adhesion; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D008024:Ligands; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3
chemical_list: D000085:Acetates; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D039302:Integrin alphaVbeta3; D039641:Integrin beta Chains; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D011498:Protein Precursors; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; C121648:SB 223245; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; C084344:integrin beta5; C072170:integrin beta6; C047981:arginyl-glycyl-aspartic acid