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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. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-04-085514v1 111/2/658    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yin, H. Articles by Du, X. Search for Related Content PubMed PubMed Citation Articles by Yin, H. Articles by Du, X. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 17, 2007 Accepted September 25, 2007 The role of Akt in the signaling pathway of the glycoprotein Ib-IX-induced platelet activation Hong Yin, Aleksandra Stojanovic, Nissim Hay, and Xiaoping Du* Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, United States * Corresponding author; email: xdu{at}uic.edu. 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. Here 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, ADP or thromboxane A2 (TXA2), in addition to their recognized roles in ADP- and TXA2-dependent secondary amplification pathways. Knockout of either 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Hajishengallis, M. Wang, and S. Liang Induction of Distinct TLR2-Mediated Proinflammatory and Proadhesive Signaling Pathways in Response to Porphyromonas gingivalis Fimbriae J. Immunol., June 1, 2009; 182(11): 6690 - 6696. [Abstract] [Full Text] [PDF] F. Morello, A. Perino, and E. Hirsch Phosphoinositide 3-kinase signalling in the vascular system Cardiovasc Res, May 1, 2009; 82(2): 261 - 271. [Abstract] [Full Text] [PDF] P. Flevaris, Z. Li, G. Zhang, Y. Zheng, J. Liu, and X. Du Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway Blood, January 22, 2009; 113(4): 893 - 901. [Abstract] [Full Text] [PDF] Y. Li, J. Lu, and E. V. Prochownik Modularity of the Oncoprotein-like Properties of Platelet Glycoprotein Ib{alpha} J. Biol. Chem., January 16, 2009; 284(3): 1410 - 1418. [Abstract] [Full Text] [PDF] E. Pluskota, N. M. Woody, D. Szpak, C. M. Ballantyne, D. A. Soloviev, D. I. Simon, and E. F. Plow Expression, activation, and function of integrin {alpha}M{beta}2 (Mac-1) on neutrophil-derived microparticles Blood, September 15, 2008; 112(6): 2327 - 2335. [Abstract] [Full Text] [PDF] H. Yin, J. Liu, Z. Li, M. C. Berndt, C. A. Lowell, and X. Du Src family tyrosine kinase Lyn mediates VWF/GPIb-IX-induced platelet activation via the cGMP signaling pathway Blood, August 15, 2008; 112(4): 1139 - 1146. [Abstract] [Full Text] [PDF] F.-T. Mu, R. K. Andrews, J. F. Arthur, A. D. Munday, S. L. Cranmer, S. P. Jackson, F. C. Stomski, A. F. Lopez, and M. C. Berndt A functional 14-3-3{zeta}-independent association of PI3-kinase with glycoprotein Ib{alpha}, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complex Blood, May 1, 2008; 111(9): 4580 - 4587. [Abstract] [Full Text] [PDF]

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