BINDING OF GALECTIN-1 TO ΑIIBΒ₃ INTEGRIN TRIGGERS "OUTSIDE-IN" SIGNALS, STIMULATES PLATELET ACTIVATION, AND CONTROLS PRIMARY HEMOSTASIS.

ROMANIUK AI; CROCI DO; LAPPONI ME; TRIBULALTI M; NEGROTTO S.S; PORIER F; CAMPETELLA O; G. A.RABINOVICH; SCHATTNER M.

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

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

0892-6638

Understanding noncanonical mechanismsof platelet activation represents an important challenge for the identification of novel therapeutic targets in bleeding disorders, thrombosis, and cancer. We previ- ously reported that galectin-1 (Gal-1), a 􏱅-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-􏱄IIb subunit of􏱄IIb􏱅3 integrin or platelets from patients with Glanzmann?s thrombasthenia syndrome (􏱄IIb􏱅3 defi- ciency), identified this integrin as a functional Gal-1 receptor in platelets. Binding of Gal-1 to platelets trig- gered the phosphorylation of 􏱅3-integrin, Syk, MAPKs, PI3K, PLC2, 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, knock- out 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 con- centrations. Impaired spreading on fibrinogen and clo