title: Binding of galectin-1 to αIIbβ₃ integrin triggers "outside-in" signals, stimulates platelet activation, and controls primary hemostasis.
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-α(IIb) subunit ofα(IIb)β(3) integrin or platelets from patients with Glanzmann's thrombasthenia syndrome (α(IIb)β(3) deficiency), identified this integrin as a functional Gal-1 receptor in platelets. Binding of Gal-1 to platelets triggered the phosphorylation of β(3)-integrin, Syk, MAPKs, PI3K, PLCγ2, thromboxane (TXA(2)) release, and Ca(2+) 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 α(IIb)β(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.
authors.affiliation: Laboratory of Experimental Thrombosis, Institute of Experimental Medicine (IMEX), National Academy of Medicine, Buenos Aires, Argentina.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Romaniuk
authors.forename: Diego O
authors.initials: DO
authors.lastname: Croci
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Lapponi
authors.forename: Maria V
authors.initials: MV
authors.lastname: Tribulatti
authors.forename: Soledad
authors.initials: S
authors.lastname: Negrotto
authors.forename: Francoise
authors.initials: F
authors.lastname: Poirier
authors.forename: Oscar
authors.initials: O
authors.lastname: Campetella
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.forename: Mirta
authors.initials: M
authors.lastname: Schattner
mesh_terms: D000818:Animals; D001760:Bleeding Time; D037483:Galectin 1 / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D013915:Thrombasthenia / Q000097:blood
chemical_list: D037483:Galectin 1; C445499:LGALS1 protein, human; D019039:Platelet Glycoprotein GPIIb-IIIa Complex