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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2728-2735. Prepublished online as a Blood First Edition Paper on December 15, 2005; DOI 10.1182/blood-2005-07-3023. This Article Full Text (PDF) All Versions of this Article: 2005-07-3023v1 107/7/2728    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 Bernardi, B. Articles by Torti, M. Search for Related Content PubMed PubMed Citation Articles by Bernardi, B. Articles by Torti, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 27, 2005 Accepted November 15, 2005 The small GTPase Rap1b regulates the cross-talk between platelet integrin 21 and integrin iib3 Bruno Bernardi, Gianni F Guidetti, Francesca Campus, Jill R Crittenden, Ann M Graybiel, Cesare Balduini, and Mauro Torti* Department of Biochemistry, University of Pavia, Center of Excellence for Applied Biology, Pavia, Italy Department of Brain and Cognitive Sciences, Massachussetts Institute of Technology, Cambridge, MA, USA * Corresponding author; email: mtorti{at}unipv.it. The involvement of the small GTPase Rap1b in platelet integrin 21-dependent outside-in signaling was investigated. Platelet adhesion to four different specific ligands for integrin 21, monomeric collagen, decorin, and collagen-derived peptides CB8(II) and CB11(II), induced a robust and rapid activation of Rap1b. This process did not require secreted ADP or thromboxane A2 production, but was critically regulated by phospholipase C (PLC)-derived second messengers. Both Ca2+ and protein kinase C were found to organize independent, but additive, pathways for Rap1b activation downstream integrin 21, which were completely blocked by inhibition of PLC with U73122. Moreover, integrin 21 engagement failed to trigger Rap1b activation in murine platelets lacking CalDAG-GEFI, a guanine nucleotide exchange factor regulated by Ca2+ and diacylglycerol, despite normal phosphorylation and activation of PLC2. In addition, CalDAG-GEFI-deficient platelets showed defective integrin 21-dependent adhesion and spreading. We found that outside-in signaling through integrin 21 triggered inside-out activation of integrin IIb3, and promoted fibrinogen binding. Similarly to Rap1b stimulation, this process occurred downstream PLC activation, and was dramatically impaired in murine platelets lacking the Rap1 exchange factor CalDAG-GEFI. These results demonstrate that Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion, and regulates the cross-talk between adhesive receptors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Yoshikawa, T. Satoh, T. Tamura, P. Wei, S. E. Bilasy, H. Edamatsu, A. Aiba, K. Katagiri, T. Kinashi, K. Nakao, et al. The M-Ras-RA-GEF-2-Rap1 Pathway Mediates Tumor Necrosis Factor-{alpha} dependent Regulation of Integrin Activation in Splenocytes Mol. Biol. Cell, August 1, 2007; 18(8): 2949 - 2959. [Abstract] [Full Text] [PDF] R. Pasvolsky, S. W. Feigelson, S. S. Kilic, A. J. Simon, G. Tal-Lapidot, V. Grabovsky, J. R. Crittenden, N. Amariglio, M. Safran, A. M. Graybiel, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets J. Exp. Med., July 9, 2007; 204(7): 1571 - 1582. [Abstract] [Full Text] [PDF] A. Strehl, I. C. A. Munnix, M. J. E. Kuijpers, P. E. J. van der Meijden, J. M. E. M. Cosemans, M. A. H. Feijge, B. Nieswandt, and J. W. M. Heemskerk Dual Role of Platelet Protein Kinase C in Thrombus Formation: STIMULATION OF PRO-AGGREGATORY AND SUPPRESSION OF PROCOAGULANT ACTIVITY IN PLATELETS J. Biol. Chem., March 9, 2007; 282(10): 7046 - 7055. [Abstract] [Full Text] [PDF] M. Holinstat, B. Voss, M. L. Bilodeau, and H. E. Hamm Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway Mol. Pharmacol., March 1, 2007; 71(3): 686 - 694. [Abstract] [Full Text] [PDF] G. F. Guidetti, B. Bernardi, L. Stefanini, F. Campus, C. Balduini, and M. 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