Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human plate independent of integrin alpha(IIb)beta(3)

Low density lipoprotein (LDL) is known to sensitize platelets to agonists v ia integrin mediated outside-in signaling (Hackeng, C, M,, Huigsloot, M,, P ladet, M, W,, Nieuwenhuis, H. K., Rijn, H, J. M, v,, and Akkerman, J, W, N, (1999) Arterioscler, Thromb, Vase, Biol,, in press). As outside in signali ng is associated with phosphorylation of p125(FAK), the effect of LDL on p1 25FAK phosphorylation in platelets was investigated. LDL induced p125FAK ph osphorylation in a dose- and time- dependent manner. The phosphorylation wa s independent of ligand binding to integrin alpha(IIb)beta(3) and aggregati on, such in contrast to Lu-thrombin-induced p125FAK phosphorylation, that c ritically depended on platelet aggregation, Platelets from patients with Gl anzmann's thrombastenia showed the same LDL- induced phosphorylation of p12 5(FAK) as control platelets, whereas alpha-thrombin completely failed to ph osphorylate the kinase in the patients platelets. LDL signaling to p125FAK was independent of integrin alpha(2)beta(1), the Fc gamma RII receptor, and the lysophosphatidic acid receptor and not affected by inhibitors of cyclo oxygenase, protein kinase C, ERK1/2 or p38(MAPK). Phosphorylation of p125(F AK) by LDL was strongly inhibited by cyclic AMP, These observations indicat e that LDL is a unique platelet agonist, as it phosphorylates p125(FAK) in platelet suspensions, under unstirred conditions and independent of integri n alpha(IIb)beta(3).