Factor Xa binding to annexin 2 mediates signal transduction via protease-activated receptor 1

Scripps Research Institute, SP-258, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Circulation Research (Impact Factor: 11.02). 03/2008; 102(4):457-64. DOI: 10.1161/CIRCRESAHA.107.167759
Source: PubMed


The serine protease zymogen factor X is converted to its catalytically active form factor Xa by the binary complex of factor VIIa bound to its cell surface receptor tissue factor (TF) or by the intrinsic Xase complex, which consists of active factors VIII (VIIIa), IX (IXa), factor X, and Ca2+. Factor Xa has procoagulant activity by conversion of prothrombin to thrombin and also induces signal transduction, either alone or in the ternary TF:VIIa:factor Xa coagulation initiation complex. Factor Xa cleaves and activates protease activated receptor (PAR)1 or -2, but factor Xa signaling efficiency varies among cell types. We show here that annexin 2 acts as a receptor for factor Xa on the surface of human umbilical vein endothelial cells and that annexin 2 facilitates factor Xa activation of PAR-1 but does not enhance coagulant function of factor Xa. Overexpression of TF abolishes annexin 2 dependence on factor Xa signaling and diminishes binding to cell surface annexin 2, whereas selectively abolishing TF promotes the annexin 2/factor Xa interaction. We propose that annexin 2 serves to regulate factor Xa signaling specifically in the absence of cell surface TF and may thus play physiological or pathological roles when factor Xa is generated in a TF-depleted environment.

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    • "The basis for the slower cleavage of the PAR2-ALP construct by GD-FXa and E2-FXa is not known and was not further investigated. However, it has been reported that FXa binds to annexin 2 by a Gla-dependent mechanism to elicit intracellular signaling responses through the activation of PAR1 (Bhattacharjee et al., 2008). Whether the higher PAR2 cleavage activity of the full-length FXa is due to its additive annexin 2-dependent cleavage of PAR2 in our over-expressing PAR2-ALP construct is not known. "
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    • "In certain circumstances factor Xa can activate PAR1 (Blanc-Brude et al., 2005; Bhattacharjee et al., 2008), and PAR2 can be activated by factor Xa (Camerer et al., 2000). Fibroblasts appear to be the only cell type in which the effects of factor Xa are mediated mainly via PAR1 and not PAR2 (Blanc-Brude et al., 2005). "
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    • "In addition to promoting blood coagulation, coagulation proteases induce signal transduction through the activation of G protein–coupled protease-activated receptors (PARs) [62], [63], [64], [65], [66]. Additionally, activated Factor X (Factor Xa) can mediate signal transduction via specific binding to annexin 2 [67]. Endothelial lipase (LIPG) is involved in lipoprotein metabolism and is elevated in inflammation [68], [69]. "
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