PlAPolymorphism of Integrin β3Differentially Modulates Cellular Migration on Extracellular Matrix Proteins

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Abstract
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 (PlA) 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 αIIbβ3 cells to fibronectin and vitronectin were not statistically different between the Leu33 and Pro33 cells. However, CHO cells with the Pro33 (PlA2) polymorphism had an enhanced haptotactic migratory response to fibrinogen and von Willebrand Factor. This enhanced migration (1) could be blocked by the αIIbβ3-complex–specific neutralizing mAb 10E5, by 7E3, a neutralizing mAb specific for the β3 integrin, and by the αIIbβ3-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 αvβ3 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 α subunit influences the substrate specificity of this genetic effect.