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 Rho guanine-nucleotide exchange factor (GEF [LARG]), a RhoA GEF, 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 the absence of LARG results in a marked reduction in aggregation and dense-granule secretion in response to the thromboxane mimetic U46619 and proteinase-activated receptor 4-activating peptide, AYPGKF, but not to adenosine diphosphate. 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 the absence of LARG, although basal activity was reduced, suggesting that LARG may play a housekeeper 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.
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Authors | C M Williams, M T Harper, R Goggs, T G Walsh, S Offermanns, A W Poole |
Journal | Journal of thrombosis and haemostasis : JTH
(J Thromb Haemost)
Vol. 13
Issue 11
Pg. 2102-7
(Nov 2015)
ISSN: 1538-7836 [Electronic] England |
PMID | 26334261
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. |
Chemical References |
- Arhgef12 protein, mouse
- Chlorides
- Ferric Compounds
- Oligopeptides
- Rho Guanine Nucleotide Exchange Factors
- alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine
- Adenosine Diphosphate
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
- RhoA protein, mouse
- rho GTP-Binding Proteins
- rhoA GTP-Binding Protein
- ferric chloride
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Topics |
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
(pharmacology)
- Adenosine Diphosphate
(pharmacology)
- Animals
- Blood Platelets
(drug effects, metabolism)
- Cell Degranulation
(drug effects)
- Chlorides
(toxicity)
- Crosses, Genetic
- Ferric Compounds
(toxicity)
- Gene Knockout Techniques
- Mice
- Mice, Knockout
- Oligopeptides
(pharmacology)
- Organ Specificity
- Platelet Activation
(physiology)
- Platelet Aggregation
- Rho Guanine Nucleotide Exchange Factors
(blood, deficiency, genetics, physiology)
- Thrombosis
(blood, chemically induced)
- rho GTP-Binding Proteins
(metabolism)
- rhoA GTP-Binding Protein
(metabolism)
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