BINDING OF GALECTIN-1 TO ALPHAIIB BETA3 INTEGRIN TRIGGERS OUTSIDE-IN SIGNALS, STIMULATES PLATELET ACTIVATION AND CONTROLS PRIMARY HEMOSTASIS

ROMANIUK MA; CROCI DO; LAPPONI MJ; TRIBULATTI MV; NEGROTTO S; POIRIER F; CAMPETELLA O; RABINOVICH GA; SCHATTNER M.

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2012 vol. 26 p. 2788 - 2798

0892-6638

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 ¥â-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-¥á(IIb) subunit of¥á(IIb)¥â(3) integrin or platelets from patients with Glanzmann¢¥s thrombasthenia syndrome (¥á(IIb)¥â(3) deficiency), identified this integrin as a functional Gal-1 receptor in platelets. Binding of Gal-1 to platelets triggered the phosphorylation of ¥â(3)-integrin, Syk, MAPKs, PI3K, PLC¥ã2, 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 ¥á(IIb)¥â(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.