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

Christopher M Williams, Matthew T Harper, Robert A N Goggs, Tony G Walsh, S Offermanns, Alastair W Poole

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
455 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)2102-2107
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number11
Early online date20 Oct 2015
DOIs
Publication statusPublished - 6 Nov 2015

Keywords

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

Fingerprint Dive into the research topics of 'Leukemia-associated Rho guanine-nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice'. Together they form a unique fingerprint.

Cite this