Pl^A polymorphism of integrin β₃ differentially modulates cellular migration on extracellular matrix proteins

Objective - Cell migration is central to multiple physiological and pathologic processes and involves interactions between integrins on the cell surface and the extracellular matrix. The Leu33Pro (Pl^A) polymorphism of integrin β₃ has been reported to be associated with a greater rate of restenosis after angioplasty, a process involving endothelial and smooth muscle cell migration. We have addressed the possibility that the Leu33Pro polymorphism could modify the migratory behavior of Chinese hamster ovary (CHO) cells expressing the β₃-containing integrin complexes. Methods and Results - Haptotactic migratory responses of CHO α_IIbβ₃ cells to fibronectin and vitronectin were not statistically different between the Leu33 and Pro33 cells. However, CHO cells with the Pro33 (Pl^A2) polymorphism had an enhanced haptotactic migratory response to fibrinogen and von Willebrand Factor. This enhanced migration (1) could be blocked by the α_IIbβ₃-complex-specific neutralizing mAb 10E5 by 7E3, a neutralizing mAb specific for the β₃ integrin, and by the α_IIbβ₃-blocking peptide Integrilin; (2) was not observed with a CHO cell line expressing an activating β₃ Cys435 to Ala mutation; and (3) was attributable to increased activity of mitogen-activated protein kinase and cyclooxygenase. CHO cell lines expressing the Pro33 isoform of ay/33 a,p, had an enhanced haptotactic migratory response to vitronectin and osteopontin but not fibrinogen. Conclusions - The Leu33Pro polymorphism alters the migratory behavior of cells on extracellular matrix substrates, and the a subunit influences the substrate specificity of this genetic effect.