title: Annexin A5 down-regulates surface expression of tissue factor: a novel mechanism of regulating the membrane receptor repertoir.
abstract: Phosphatidylserine (PtdSer) is exposed on the external leaflet of the plasma membrane during apoptosis. The protein annexin A5 (anxA5) shows high affinity for PtdSer. When anxA5 binds to the PtdSer-expressing membranes during apoptosis, it crystallizes as an extended two-dimensional network and activates thereby a novel portal of cell entry that results in the internalization of the PtdSer-expressing membrane patches. This novel pathway of cell entry is potentially involved in the regulation of the surface expression of membrane receptors. In this study we report the regulation of surface expression of the initiator of blood coagulation tissue factor (TF) by this novel pathway of cell entry. AnxA5 induces the internalization of tissue factor expressed on the surface of apoptotic THP-1 macrophages. This down-regulation depends on the abilities of anxA5 to bind to PtdSer and to form a two-dimensional crystal at the membrane. We furthermore show that THP-1 cells produce and externalize anxA5 that cause the internalization of TF in an autocrine type of mechanism. We extended our in vitro work to the in vivo situation and show in a mouse model that anxA5 causes the down-regulation of TF expression by smooth muscle cells of the media of the carotid artery that was mechanically injured. In conclusion, anxA5 down-regulates surface-expressed TF by activating the novel portal of cell entry. This mechanism may be part of a more general autocrine function of anxA5 to regulate the plasma membrane receptor repertoir under stress conditions associated with the surface expression of PtdSer.
authors.affiliation: Department of Biochemistry, University of Maastricht, P. O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Bennaghmouch
authors.forename: Heidi
authors.initials: H
authors.lastname: Kenis
authors.forename: Theo
authors.initials: T
authors.lastname: Lindhout
authors.forename: Tilman
authors.initials: T
authors.lastname: Hackeng
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
authors.forename: Leo
authors.initials: L
authors.lastname: Hofstra
authors.forename: Chris
authors.initials: C
authors.lastname: Reutelingsperger
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis; D005047:Etoposide / Q000494:pharmacology; D005167:Factor VII / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010718:Phosphatidylserines / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; D005047:Etoposide; D005167:Factor VII; D013925:Thromboplastin; D013755:Tetradecanoylphorbol Acetate