The endothelial cell annexin A2 system and vascular fibrinolysis.
Vascular endothelial cell surface expression of annexin A2 and its binding partner p11 is a key element in maintaining fibrinolytic balance on blood vessel surfaces. In the recent decade, investigators have made significant progress toward understanding the mechanisms that regulate heterotetrameric (A2*p11)(2) receptor translocation from the cytoplasm to the outer cell surface. Accumulating evidence now shows that heterotetrameric (A2*p11)(2) cell surface expression is a dynamic process that modulates plasmin activation during periods of vascular stress or injury, and is independent of the classical endoplasmic reticulum-Golgi pathway. Translocation of heterotetrameric (A2*p11)(2) is facilitated both by src-kinase mediated phosphorylation of A2 at tyrosine 23, and by expression of and partnering with p11. In the absence of A2 both in vivo and in vitro, p11 is expressed at very low levels in endothelial cells, because unpartnered p11 is polyubiquitinated and rapidly degraded through a proteasome-dependent mechanism. A2 directly binds and stabilizes intracellular p11 by masking an autonomous polyubiquitination signal on p11. This modulatory role of A2 binding prevents accumulation of unpartnered p11 within the endothelial cell, and ultimately suggests that the regulation of heterotetrameric (A2*p11)(2) receptor surface expression is precisely attuned to the intracellular level of p11.
Dassah
MaryAnn
M
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Deora
Arun B
AB
He
Kaili
K
Hajjar
Katherine A
KA
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D001665:Binding Sites; D042783:Endothelial Cells / Q000378:metabolism*; D005341:Fibrinolysin / Q000737:chemistry; D005342:Fibrinolysis; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D017306:Annexin A2; D055293:Receptors, Urokinase Plasminogen Activator; D025801:Ubiquitin; D010958:Plasminogen; D005341:Fibrinolysin