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Leukemia-associated Rho guanine-nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)2102-2107
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number11
Early online date20 Oct 2015
DOIs
DateAccepted/In press - 3 Aug 2015
DateE-pub ahead of print - 20 Oct 2015
DatePublished (current) - 6 Nov 2015

Abstract

Background: RhoA is an important regulator of platelet responses downstream of Gα13, yet we still know little about its regulation in platelets. Leukemia-Associated RhoGEF (LAR6G), a RhoAGEF, is highly expressed in platelets and may constitute a major upstream activator of RhoA. To this end, it is important to determine the role of LARG in platelet function and thrombosis.

Methods and Results: Using a platelet-specific gene knockout, we show that absence of LARG results in a marked reduction in aggregation and dense-granule secretion in response to the thromboxane mimetic, U46619, and PAR4-activating peptide, AYPGKF, but not to ADP. In a ferric chloride thrombosis model in vivo, this translated into a defect, under mild injury conditions. Importantly, agonist-induced RhoA activation was not affected by absence of LARG, although basal activity was reduced, suggesting that LARG may play a house-keeper role in regulating constitutive RhoA activity.

Conclusions:LARG plays an important role in platelet function and thrombosis in vivo. However, although LARG may have a role in regulating the resting activation state of RhoA, its role in regulating platelet function may principally be through RhoA-independent pathways, possibly through other Rho-family members.

    Research areas

  • gene knockout, Larg protein, mouse, mouse, platelets, RhoA protein, mouse, thrombosis

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  • Williams_et_al_2015_Journal_of_Thrombosis_and_Haemostasis

    Rights statement: This is the open access published version of the following article: Williams CM, Harper MT, Goggs R, Walsh TG, Offermanns S, Poole AW. Leukemia-associated Rho guanine-nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice. J Thromb Haemost 2015; 13: 2102–7, which has been published in final form at DOI: 10.1111/jth.13129.

    Final published version, 412 KB, PDF document

    Licence: CC BY

  • 2015 08, Williams 48430238

    Other version, 290 KB, PDF document

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