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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5260-5269.
Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2006-10-054015.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Ligand density dramatically affects integrin  IIbß3-mediated platelet signaling and spreading
Markéta Jirou ková1,
Jyoti K. Jaiswal2, and
Barry S. Coller1
Laboratory of 1 Blood and Vascular Biology and
2 Cellular Biophysics, Rockefeller University, New York, NY
The impact of ligand density on integrin-mediated cell adhesion and outside-in signaling is not well understood. Using total internal reflection fluorescent microscopy, conformation-specific antibodies, and Ca2+ flux measurements, we found that the surface density of fibrinogen affects  IIbß3-mediated platelet signaling, adhesion, and spreading. Adhesion to fibrinogen immobilized at low density leads to rapid increases in cytosolic Ca2+ and sequential formation of filopodia and lamellipodia. In contrast, adhesion to high-density fibrinogen results in transient or no increases in Ca2+ and simultaneous formation of filopodia and lamellipodia. IIbß3 receptors at the basal surface of platelets engage fibrinogen in a ringlike pattern at the cell edges under both conditions. This engagement is, however, more dynamic and easily reversed on high-density fibrinogen. Src and Rac activity and actin polymerization are important for adhesion to low-density fibrinogen, whereas PKC/PI3 kinases contribute to platelet spreading on high-density fibrinogen. We conclude that 2 fundamentally different signaling mechanisms can be initiated by a single integrin receptor interacting with the same ligand when it is immobilized at different densities.
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