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In this study, we show that the G protein-coupled receptor agonist thrombin, the glycoprotein VI agonist convulxin, and the cytokine receptor Mpl agonist thrombopoietin (TPO) are able to induce activation of RAS in human platelets. Recruitment ofGRB2 by tyrosine-phosphorylated proteins in response to TPO and convulxin but not by thrombin occurred with a similar time-course to RAS acti-vation, consistent with a causal relationship. | Eur. J. Biochem. 269 1511-1517 2002 FEBS 2002 Regulation of RAS in human platelets Evidence that activation of RAS is not sufficient to lead to ERK1-2 phosphorylation David Tulasne1 Teresa Bori2 and Steve P. Watson1 1 Department of Pharmacology University of Oxford UK 2 Division of Medical Sciences The Medical School University of Birmingham Edgbaston UK In this study we show that the G protein-coupled receptor agonist thrombin the glycoprotein VI agonist convulxin and the cytokine receptor Mpl agonist thrombopoietin TPO are able to induce activation of RAS in human platelets. Recruitment of GRB2 by tyrosine-phosphorylated proteins in response to TPO and convulxin but not by thrombin occurred with a similar time-course to RAS activation consistent with a causal relationship. On the other hand activation of ERK2 by thrombin and convulxin is delayed and also inhibited by the protein kinase C inhibitor Ro-31 8220 whereas RAS activation is unaffected. Further evidence for differential regulation of RAS and ERK is provided by the observations that TPO which activates RAS but not protein kinase C does not activate ERK and that the inhibitor of SRC kinases PP1 inhibits activation of RAS but not ERK2 in response to thrombin. Our results demonstrate that activation of RAS is not necessarily coupled to ERK in human platelets. Keywords ERK glycoprotein VI platelet protein kinase C RAS signalling thrombin thrombopoietin. RAS is a ubiquitously expressed GTPase protein which is activated following conversion from a GDP to GTP-bound state. GDP-GTP exchange is stimulated by SOS which is constitutively associated through its proline rich domain to the SH3 domains of the adapter GRB2. The Src homology SH 2 domain of GRB2 is able to bind phosphorylated tyrosine residues on tyrosine kinase receptors or membrane-localized adapters. Localization of GRB2-SOS complex to the plasma membrane following this recruitment promotes RAS activation 1-3 . RAS was discovered as an oncogene which was