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J. Biol. Chem., Vol. 283, Issue 4, 2297-2306, January 25, 2008

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Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets^*

Meike Hoffmeister, Pavel Riha¹, Olga Neumüller, Oliver Danielewski, Jan Schultess, and Albert P. Smolenski²

From the Institute of Biochemistry II, University of Frankfurt Medical School, 60590 Frankfurt, Germany and the First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic

GTPase-activating proteins are required to terminate signaling by Rap1, a small guanine nucleotide-binding protein that controls integrin activity and cell adhesion. Recently, we identified Rap1GAP2, a GTPase-activating protein of Rap1 in platelets. Here we show that 14-3-3 proteins interact with phosphorylated serine 9 at the N terminus of Rap1GAP2. Platelet activation by ADP and thrombin enhances serine 9 phosphorylation and increases 14-3-3 binding to endogenous Rap1GAP2. Conversely, inhibition of platelets by endothelium-derived factors nitric oxide and prostacyclin disrupts 14-3-3 binding. These effects are mediated by cGMP- and cAMP-dependent protein kinases that phosphorylate Rap1GAP2 at serine 7, adjacent to the 14-3-3 binding site. 14-3-3 binding does not change the GTPase-activating function of Rap1GAP2 in vitro. However, 14-3-3 binding attenuates Rap1GAP2 mediated inhibition of cell adhesion. Our findings define a novel crossover point of activatory and inhibitory signaling pathways in platelets.

Received for publication, August 16, 2007 , and in revised form, October 31, 2007.

^* This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 553). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a grant from the Ministry of Education, Youth, and Sports, Czech Republic.

² To whom correspondence should be addressed: Institute of Biochemistry II, University of Frankfurt Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Tel.: 49-69-6301-5569; Fax: 49-69-6301-5577; E-mail: smolenski{at}biochem2.de.

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