title: Factor Xa binding to annexin 2 mediates signal transduction via protease-activated receptor 1.
abstract: 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.
authors.affiliation: Scripps Research Institute, SP-258, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA. gourab@scripps.edu
authors.forename: Gourab
authors.initials: G
authors.lastname: Bhattacharjee
authors.forename: Jasimuddin
authors.initials: J
authors.lastname: Ahamed
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Edgington
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D001777:Blood Coagulation / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D017434:Protein Structure, Tertiary; D044463:Receptor, PAR-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D044463:Receptor, PAR-1; D013925:Thromboplastin; D015951:Factor Xa; D008239:Lysine