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Molecular and Cellular Biology, February 2000, p. 779-785, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Sequential Regulation of the Small GTPase Rap1 in Human Platelets

Barbara Franke,1,2 Miranda van Triest,1 Kim M. T. de Bruijn,1 Gijsbert van Willigen,2 H. Karel Nieuwenhuis,2 Claude Negrier,3 Jan-Willem N. Akkerman,2 and Johannes L. Bos1,*

Laboratory for Physiological Chemistry and Centre for Biomedical Genetics1 and Department of Haematology,2 UMC Utrecht, Utrecht, The Netherlands, and Centre de Traitement de l'Hemophilie, Hopital Edouard Herriot, Lyon, France3

Received 6 August 1999/Returned for modification 13 September 1999/Accepted 25 October 1999

Rap1, a small GTPase of the Ras family, is ubiquitously expressed and particularly abundant in platelets. Previously we have shown that Rap1 is rapidly activated after stimulation of human platelets with alpha -thrombin. For this activation, a phospholipase C-mediated increase in intracellular calcium is necessary and sufficient. Here we show that thrombin induces a second phase of Rap1 activation, which is mediated by protein kinase C (PKC). Indeed, the PKC activator phorbol 12-myristate 13-acetate induced Rap1 activation, whereas the PKC-inhibitor bisindolylmaleimide inhibited the second, but not the first, phase of Rap1 activation. Activation of the integrin alpha IIbbeta 3, a downstream target of PKC, with monoclonal antibody LIBS-6 also induced Rap1 activation. However, studies with alpha IIbbeta 3-deficient platelets from patients with Glanzmann's thrombasthenia type 1 show that alpha IIbbeta 3 is not essential for Rap1 activation. Interestingly, induction of platelet aggregation by thrombin resulted in the inhibition of Rap1 activation. This downregulation correlated with the translocation of Rap1 to the Triton X-100-insoluble, cytoskeletal fraction. We conclude that in platelets, alpha -thrombin induces Rap1 activation first by a calcium-mediated pathway independently of PKC and then by a second activation phase mediated by PKC and, in part, integrin alpha IIbbeta 3. Inactivation of Rap1 is mediated by an aggregation-dependent process that correlates with the translocation of Rap1 to the cytoskeletal fraction.

* Corresponding author. Mailing address: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31 30 2538977. Fax: 31 30 2539035. E-mail: j.l.bos{at}med.uu.nl.

Molecular and Cellular Biology, February 2000, p. 779-785, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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