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Blood, 15 January 2008, Vol. 111, No. 2, pp. 658-665.
Prepublished online as a Blood First Edition Paper on October 3, 2007; DOI 10.1182/blood-2007-04-085514.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The role of Akt in the signaling pathway of the glycoprotein Ib-IX–induced platelet activation
Hong Yin1,
Aleksandra Stojanovic1,
Nissim Hay1, and
Xiaoping Du1
1 Departments of Pharmacology and of Biochemistry and Molecular Genetics, University of Illinois at Chicago
The platelet von Willebrand factor (vWF) receptor, glycoprotein Ib-IX (GPIb-IX), mediates platelet adhesion and induces signaling leading to integrin activation. Phosphoinositol 3-kinase (PI3K) is important in GPIb-IX–mediated signaling. PI3K–dependent signaling mechanisms, however, are unclear. We show that GPIb-IX–induced platelet aggregation and stable adhesion under flow were impaired in mouse platelets deficient in PI3K effectors, Akt1 and Akt2, and in human platelets treated with an Akt inhibitor, SH-6. Akt1 and Akt2 play important roles in early GPIb-IX signaling independent of Syk, adenosine diphosphate (ADP), or thromboxane A2 (TXA2), in addition to their recognized roles in ADP- and TXA2–dependent secondary amplification pathways. Knockout of Akt1 or Akt2 diminished platelet spreading on vWF but not on immobilized fibrinogen. Thus, Akt1 and Akt2 are both required only in the GPIb-IX–mediated integrin activation (inside-out signaling). In contrast, PI3K inhibitors abolished platelet spreading on both vWF and fibrinogen, indicating a role for PI3K in integrin outside-in signaling distinct from that in GPIb-IX–mediated inside-out signaling. Furthermore, Akt1- or Akt2-deficiency diminished vWF–induced cGMP elevation, and their inhibitory effects on GPIb-IX–dependent platelet adhesion were reversed by exogenous cGMP. Thus, Akt1 and Akt2 mediate GPIb-IX signaling via the cGMP–dependent signaling pathway.
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