Title: Binding of galectin‐1 to α<sub>IIb</sub>β<sub>3</sub>integrin triggers “outside‐in” signals, stimulates platelet activation, and controls primary hemostasis
Abstract: The FASEB JournalVolume 26, Issue 7 p. 2788-2798 Research CommunicationFree to Read Binding of galectin-1 to αIIbβ3 integrin triggers "outside-in" signals, stimulates platelet activation, and controls primary hemostasis Maria A. Romaniuk, Maria A. Romaniuk Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorDiego O. Croci, Diego O. Croci Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME)Search for more papers by this authorMaria J. Lapponi, Maria J. Lapponi Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorMaria V. Tribulatti, Maria V. Tribulatti Institute of Biotechnological Investigations-Institute of Technology of Chascomús-National University of San Martín, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, ArgentinaSearch for more papers by this authorSoledad Negrotto, Soledad Negrotto Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorFrancoise Poirier, Francoise Poirier Jacques Monod Institute, Unité Mixte de Recherche (UMR)—Centre National de la Recherche Scientifique (CNRS) 7592, Paris Diderot University, Paris, FranceSearch for more papers by this authorOscar Campetella, Oscar Campetella Institute of Biotechnological Investigations-Institute of Technology of Chascomús-National University of San Martín, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, ArgentinaSearch for more papers by this authorGabriel A. Rabinovich, Corresponding Author Gabriel A. Rabinovich [email protected] Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME)These authors contributed equally to this work.Correspondence: M.S., Instituto de Medicina Experimental (IMEX), CONICET/ANM, Pacheco de Melo 3081, Buenos Aires (1425), Argentina. E-mail: [email protected]; G.A.R., Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires (1428), Argentina. E-mail: [email protected]Search for more papers by this authorMirta Schattner, Corresponding Author Mirta Schattner [email protected] Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineThese authors contributed equally to this work.Correspondence: M.S., Instituto de Medicina Experimental (IMEX), CONICET/ANM, Pacheco de Melo 3081, Buenos Aires (1425), Argentina. E-mail: [email protected]; G.A.R., Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires (1428), Argentina. E-mail: [email protected]Search for more papers by this author Maria A. Romaniuk, Maria A. Romaniuk Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorDiego O. Croci, Diego O. Croci Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME)Search for more papers by this authorMaria J. Lapponi, Maria J. Lapponi Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorMaria V. Tribulatti, Maria V. Tribulatti Institute of Biotechnological Investigations-Institute of Technology of Chascomús-National University of San Martín, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, ArgentinaSearch for more papers by this authorSoledad Negrotto, Soledad Negrotto Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineSearch for more papers by this authorFrancoise Poirier, Francoise Poirier Jacques Monod Institute, Unité Mixte de Recherche (UMR)—Centre National de la Recherche Scientifique (CNRS) 7592, Paris Diderot University, Paris, FranceSearch for more papers by this authorOscar Campetella, Oscar Campetella Institute of Biotechnological Investigations-Institute of Technology of Chascomús-National University of San Martín, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, ArgentinaSearch for more papers by this authorGabriel A. Rabinovich, Corresponding Author Gabriel A. Rabinovich [email protected] Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME)These authors contributed equally to this work.Correspondence: M.S., Instituto de Medicina Experimental (IMEX), CONICET/ANM, Pacheco de Melo 3081, Buenos Aires (1425), Argentina. E-mail: [email protected]; G.A.R., Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires (1428), Argentina. E-mail: [email protected]Search for more papers by this authorMirta Schattner, Corresponding Author Mirta Schattner [email protected] Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of MedicineThese authors contributed equally to this work.Correspondence: M.S., Instituto de Medicina Experimental (IMEX), CONICET/ANM, Pacheco de Melo 3081, Buenos Aires (1425), Argentina. E-mail: [email protected]; G.A.R., Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires (1428), Argentina. E-mail: [email protected]Search for more papers by this author First published: 27 March 2012 https://doi.org/10.1096/fj.11-197541Citations: 30 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat ABSTRACT 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 β-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-αIIb subunit of αIIbβ3 integrin or platelets from patients with Glanzmann's thrombasthenia syndrome (αIIbβ3 deficiency), identified this integrin as a functional Gal-1 receptor in platelets. Binding of Gal-1 to platelets triggered the phosphorylation of β3-integrin, Syk, MAPKs, PI3K, PLCγ2, thromboxane (TXA2) 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 αIIbβ3 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 αIIbβ3 integrin triggers "outside-in" signals, stimulates platelet activation, and controls primary hemostasis. 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