Low Density Lipoprotein Phosphorylates the Focal Adhesion-associated Kinase p125FAK in Human Platelets Independent of Integrin αIIbβ3

Low density lipoprotein (LDL) is known to sensitize platelets to agonists via integrin mediated outside-in signaling (Hackeng, C. M., Huigsloot, M., Pladet, M. W., Nieuwenhuis, H. K., Rijn, H. J. M. v., and Akkerman, J. W. N. (1999) Arterioscler. Thromb. Vasc. Biol., in press). As outside in signaling is associated with phosphorylation of p125FAK, the effect of LDL on p125FAK phosphorylation in platelets was investigated. LDL induced p125FAK phosphorylation in a dose- and time- dependent manner. The phosphorylation was independent of ligand binding to integrin αIIbβ3 and aggregation, such in contrast to α-thrombin-induced p125FAK phosphorylation, that critically depended on platelet aggregation. Platelets from patients with Glanzmann's thrombastenia showed the same LDL- induced phos- phorylation of p125FAK as control platelets, whereas α-thrombin completely failed to phosphorylate the kinase in the patients platelets. LDL signaling to p125FAK was independent of integrin α2β1, the FcγRII receptor, and the lysophosphatidic acid receptor and not affected by inhibitors of cyclooxygenase, protein kinase C, ERK1/2 or p38MAPK. Phosphorylation of p125FAK by LDL was strongly inhibited by cyclic AMP. These observations indicate that LDL is a unique platelet agonist, as it phosphorylates p125FAKin platelet suspensions, under unstirred conditions and independent of integrin αIIbβ3.