Pl^APolymorphism of Integrin β₃Differentially Modulates Cellular Migration on Extracellular Matrix Proteins

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 (Pl A ) polymorphism of integrin ␤ 3 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 ␤ 3 -containing integrin complexes. Methods and Results-Haptotactic migratory responses of CHO ␣ IIb ␤ 3 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 ␣ IIb ␤ 3 -complex-specific neutralizing mAb 10E5, by 7E3, a neutralizing mAb specific for the ␤ 3 integrin, and by the ␣ IIb ␤ 3 -blocking peptide Integrilin; (2) was not observed with a CHO cell line expressing an activating ␤ 3 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 ␣ v ␤ 3 had an enhanced haptotactic migratory response to vitronectin and osteopontin but not fibrinogen. Conclusions-The

Junctional adhesion molecule-A-induced endothelial cell migration on vitronectin is integrin αvβ3 specific

“…JAM-A regulates ␣ v ␤ 3 -dependent MAPK activation It is well documented that activation of ␣ v ␤ 3 leads to MAPK activation and endothelial cell migration (Camenisch et al, 2002;Degryse et al, 2001;Sajid et al, 2002). Because JAM-A overexpression leads to HUVEC migration, we thereby reasoned that JAM-A might also be involved in MAPK activation.…”

Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin

“…The protein carrying the Pl A2 allele has been shown to have increased and more stable interactions with fibrinogen, 35 enhanced platelet aggregability and thrombin generation, 36 -38 and enhanced cell migration. 39 Further, the Pl A2 allele has been associated with coronary thrombosis, 40,41 stroke, 42,43 and myocardial infarction. 44,45 Studies of ITGB3 polymorphisms and whole blood serotonin in patients with cardiovascular diseases and controls will be required to evaluate whether altered serotonin levels mediate the association between Pl A2 and cardiovascular phenotypes.…”

Thrombophilia in Assisted Reproductive Technology — Place and Needs of Thromboprophylaxis

“…β3 subunit also is a part of other integrins. One of them is αIIbβ3 integrin, involved in the process of platelet aggregation [31]. One common polymorphism in the gene sequence of β3 subunit (1567 T>C) was found to increase the subunit affinity to ligands and could influence the platelet interaction, as well as the adhesion process during implantation.…”

“…The impact of increased platelet activity on implantation process is particularly embarrassed, because investigated polymorphism A1/A2 concerns beta3 subunits of platelet integrin alphaIIb/beta3, which is also part of integrin αvβ3, related with embryo adhesion to endometrium [78]. An in vitro investigation has found that changes in the peptide structure of beta3 subunit have had influence on the receptor activity to its ligandsosteopontin and vitronectin [31]. Sajid et al [31] established that cell lines which expressed alphaV/beta3 receptor with PL A1/A2 had an enhanced haptotactic migratory response to vitronectin and osteopontin.…”

“…An in vitro investigation has found that changes in the peptide structure of beta3 subunit have had influence on the receptor activity to its ligandsosteopontin and vitronectin [31]. Sajid et al [31] established that cell lines which expressed alphaV/beta3 receptor with PL A1/A2 had an enhanced haptotactic migratory response to vitronectin and osteopontin. As the initiation of fetus adhesion to the endometrium has been connected mainly with the activity of integrin alphaV/beta3, polymorphism A1/A2 could play a significant role not only in platelet aggregation, but also in adhesion and endometrium to embryo interaction during implantation.…”