Journal
FASEB JOURNAL
Volume 26, Issue 7, Pages 2788-2798Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-197541
Keywords
inflammation; glycobiology
Categories
Funding
- Argentinean National Agency for Science and Technology [PICTs 1990, 0369, 870]
- Aniara
- University of Buenos Aires
- Mizutani Foundation for Glycoscience
- National Multiple Sclerosis Society
- Sales Foundation
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Understanding noncanonical mechanisms of platelet activation represents an important challenge for the identification of novel therapeutic targets in bleeding disorders, thrombosis, and cancer. We previously reported that galectin-1 (Gal-1), a beta-galactoside-binding protein, triggers platelet activation in vitro. Here we investigated the molecular mechanisms underlying this function and the physiological relevance of endogenous Gal-1 in hemostasis. Mass spectrometry analysis, as well as studies using blocking antibodies against the anti-alpha(IIb) subunit of alpha(IIb)beta(3) integrin or platelets from patients with Glanzmann's thrombasthenia syndrome (alpha(IIb)beta(3) deficiency), identified this integrin as a functional Gal-1 receptor in platelets. Binding of Gal-1 to platelets triggered the phosphorylation of beta(3)-integrin, Syk, MAPKs, PI3K, PLC gamma 2, thromboxane (TXA(2)) release, and Ca2+ mobilization. Not only soluble but also immobilized Gal-1 promoted platelet activation. Gal-1-deficient (Lgals1(-/-)) mice showed increased bleeding time (P<0.0002, knockout vs. wild type), which was not associated with an abnormal platelet count. Lgals1(-/-) platelets exhibited normal aggregation to PAR4, ADP, arachidonic acid, or collagen but abnormal ATP release at low collagen concentrations. Impaired spreading on fibrinogen and clot retraction with normal levels of alpha(IIb)beta(3) was also observed in Lgals1(-/-) platelets, indicating a failure in the outside-in signaling through this integrin. This study identifies a noncanonical mechanism, based on galectin-integrin interactions, for regulating platelet activation.-Romaniuk, M. A., Croci, D. O., Lapponi, M. J., Tribulatti, M. V., Negrotto, S., Poirier, F., Campetella, O., Rabinovich, G. A., Schattner, M. Binding of galectin-1 to alpha(IIb)beta(3) integrin triggers outside-in signals, stimulates platelet activation, and controls primary hemostasis. FASEB J. 26, 2788-2798 (2012). www.fasebj.org
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