Specific binding between the v/33 integrin and an RGD domain of the P2Y2 nucleotide receptor


Angiogenesis is essential for the growth of solid tumors and its inhibition has become an important approach for the treatment of cancer. Recent studies have indicated that the integrin receptor av/33 is expressed in angiogenic endothelial cells and that antagonists of v/3 (e.g., soluble anti-av/33 antibodies and certain RGD-containing peptides) inhibit p53 activity in these cells, leading to apoptosis and the atrophy of newly formed blood vessels. The G proteincoupled P2Y2 receptor, which is activated by ATP or UTP and is expressed in endothelium as well as epithelium and a variety of other tissues, contains an RGD integrin-binding motif in the first extra;cellular loop. To determine whether the RGD domain of the P2Y2 receptor binds to the v/33 integrin, an 18 amino acid peptide encompassing this domain (P2Y293-n) was coupled to aldehyde-modified fluorescent beads and incubated with K562 cells, a human erythroleukemia cell line that expresses 5, av, /31, /33, and /5 lutegrin subunits. The results showed that binding of P2Y293-lm-coated beads to K562 cells was comparable to the binding of fibronectin- and vitronectin-coated beads and was inhibited by soluble P2Y293-H. Furthermore, P2Y293-ncoated bead binding to K562 cells was inhibited by monoclonai antibodies to the v3 integrin or to the integrin associated protein (IAP), but not by antibodies to the a5/31 integrin or by GRGDSP, an a5/31 antagonist. This study indicates that the RGD domain of the P2Y2 receptor binds to the av/33 lutegrin but not the a5/31 integrin and suggests that this peptide may be useful for anti-angiogenic therapies. (Supported by the American Heart Association).

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FASEB Journal