The PlA2 polymorphism of integrin β3 enhances outside-in signaling and adhesive functions
K. Vinod Vijayan, Pascal J. Goldschmidt-Clermont, Christine Roos, Paul F. Bray
K. Vinod Vijayan, Pascal J. Goldschmidt-Clermont, Christine Roos, Paul F. Bray
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The PlA2 polymorphism of integrin β3 enhances outside-in signaling and adhesive functions

Abstract

Genetic factors are believed to influence the development of arterial thromboses. Because integrin αIIbβ3 plays a crucial role in thrombus formation, we analyzed receptor adhesive properties using Chinese hamster ovary and human kidney embryonal 293 cells overexpressing the PlA1 or PlA2 polymorphic forms of αIIbβ3. Soluble fibrinogen binding was no different between PlA1 and PlA2 cells, either in a resting state or when αIIbβ3 was activated with anti-LIBS6. PlA1 and PlA2 cells bound equivalently to immobilized fibronectin. In contrast, significantly more PlA2 cells bound to immobilized fibrinogen in an αIIbβ3-dependent manner than did PlA1 cells. Disruption of the actin cytoskeleton by cytochalasin D abolished the increased binding of PlA2 cells. Compared with PlA1 cells, PlA2 cells exhibited a greater extent of polymerized actin and cell spreading, enhanced tyrosine phosphorylation of pp125FAK, and greater fibrin clot retraction. These adhesion differences appear to depend on a signaling mechanism sensitive to receptor occupancy. Thus, the PlA2 polymorphism altered integrin-mediated functions of adhesion, spreading, actin cytoskeleton rearrangement, and clot retraction.

Authors

K. Vinod Vijayan, Pascal J. Goldschmidt-Clermont, Christine Roos, Paul F. Bray

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Fibrin clot retraction. (a) Clot retraction of LK444 (open squares), A1 ...
Fibrin clot retraction. (a) Clot retraction of LK444 (open squares), A1 (open diamonds), or A2 (open circles) cells was performed as described in Methods. The increased fibrin clot retraction of A2 over A1 was significant at P = 0.002, P = 0.003, P = 0.004, P = 0.03 for 30, 60, 90, and 120 minutes, respectively. The results are ± SEM of 6 experiments performed. Error bars were too small to be displayed. (b) A1 cells and (c) A2 cells demonstrate that clot retraction is mediated through αIIbβ3. Cells were incubated with buffer (open squares), 10 μg/mL anti αvβ3 LM609 (open circles), or 5 μM integrelin (open diamonds), and clot retraction was performed as above. The results are ± SEM of 3 experiments performed. Error bars are too small to be displayed.