Factor Xa Binding to Annexin 2 Mediates Signal Transduction via Protease-Activated Receptor 1

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 Ca. Factor...

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Bibliographic Details
Published in:Circulation research 2008-02, Vol.102 (4), p.457-464
Main Authors: Bhattacharjee, Gourab, Ahamed, Jasimuddin, Pawlinski, Rafal, Liu, Cheng, Mackman, Nigel, Ruf, Wolfram, Edgington, Thomas S
Format: Article
Language:English
Subjects:
Animals
Annexin A2 - metabolism
Biological and medical sciences
Blood Coagulation - physiology
Cells, Cultured
Endothelial Cells - cytology
Endothelial Cells - metabolism
Factor Xa - chemistry
Factor Xa - metabolism
Fundamental and applied biological sciences. Psychology
Humans
Immunoprecipitation
Lysine - metabolism
Mice
Mice, Mutant Strains
Protein Structure, Tertiary
Receptor, PAR-1 - metabolism
Signal Transduction - physiology
Thromboplastin - metabolism
Umbilical Veins - cytology
Vertebrates: cardiovascular system
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Summary: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 Ca. 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.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.107.167759