Journal of Clinical Investigation 2015-04-01

RASA3 is a critical inhibitor of RAP1-dependent platelet activation.

Lucia Stefanini, David S Paul, Raymond F Robledo, E Ricky Chan, Todd M Getz, Robert A Campbell, Daniel O Kechele, Caterina Casari, Raymond Piatt, Kathleen M Caron, Nigel Mackman, Andrew S Weyrich, Matthew C Parrott, Yacine Boulaftali, Mark D Adams, Luanne L Peters, Wolfgang Bergmeier

Index: J. Clin. Invest. 125(4) , 1419-32, (2015)

Full Text: HTML

Abstract

The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets. The increased platelet turnover and the resulting thrombocytopenia were reversed by concomitant deletion of the gene encoding CalDAG-GEFI. Rasa3 mutant platelets were hyperresponsive to agonist stimulation, both in vitro and in vivo. Moreover, activation of Rasa3 mutant platelets occurred independently of ADP feedback signaling and was insensitive to inhibitors of P2Y12 or PI3 kinase. Together, our results indicate that RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI/RAP1 signaling and suggest that P2Y12 signaling is required to inhibit RASA3 and enable sustained RAP1-dependent platelet activation and thrombus formation at sites of vascular injury. These findings provide insight into the antithrombotic effect of P2Y12 inhibitors and may lead to improved diagnosis and treatment of platelet-related disorders.


Related Compounds

Related Articles:

Genotoxicity assessment of melamine in the in vivo Pig-a mutation assay and in a standard battery of assays.

2015-01-01

[Mutat. Res. Genet. Toxicol. Environ. Mutagen. 777 , 62-7, (2015)]

The stress response resolution assay. I. Quantitative assessment of environmental agent/condition effects on cellular stress resolution outcomes in epithelium.

2013-05-01

[Environ. Mol. Mutagen. 54(4) , 268-80, (2013)]

The stress response resolution assay. II. Quantitative assessment of environmental agent/condition effects on cellular stress resolution outcomes in epithelium.

2013-05-01

[Environ. Mol. Mutagen. 54(4) , 281-93, (2013)]

Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior.

2015-10-14

[J. Neurosci. 35 , 13975-88, (2015)]

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

2014-11-11

[Proc. Natl. Acad. Sci. U. S. A. 111(45) , E4869-77, (2014)]

More Articles...