Endothelial cell annexin A2 regulates polyubiquitination and degradation of its binding partner S100A10/p11.
The annexin A2 (A2) heterotetramer, consisting of two copies of A2 and two copies of S100A10/p11, promotes fibrinolytic activity on the surface of vascular endothelial cells by assembling plasminogen and tissue plasminogen activator (tPA) and accelerating the generation of plasmin. In humans, overexpression of A2 by acute promyelocytic leukemia cells is associated with excessive fibrinolysis and hemorrhage, whereas anti-A2 autoantibodies appear to accentuate the risk of thrombosis in patients with anti-phospholipid syndrome. Complete deficiency of A2 in mice leads to a lack of tPA cofactor activity, accumulation of intravascular fibrin, and failure to clear arterial thrombi. Within the endothelial cell, p11 is required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface. Here we show that p11 is expressed at very low levels in the absence of A2 both in vitro and in vivo. We demonstrate further that unpartnered p11 becomes polyubiquitinated and degraded via a proteasome-dependent mechanism. A2 stabilizes intracellular p11 through direct binding, thus masking an autonomous p11 polyubiquitination signal that triggers proteasomal degradation. This interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. This mechanism prevents accumulation of free p11 in the endothelial cell and suggests that regulation of tPA-dependent cell surface fibrinolytic activity is precisely tuned to the intracellular level of p11.
He
Kai-Li
KL
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
Deora
Arunkumar B
AB
Xiong
Huabao
H
Ling
Qi
Q
Weksler
Babette B
BB
Niesvizky
Ruben
R
Hajjar
Katherine A
KA
D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000235:genetics; D001323:Autoantibodies / Q000097:blood; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism*; D005337:Fibrin / Q000235:genetics / Q000378:metabolism; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics; D006470:Hemorrhage / Q000097:blood / Q000209:etiology / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000150:complications / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D001323:Autoantibodies; D005337:Fibrin; D005341:Fibrinolysin; D015688:Oncogene Protein pp60(v-src); D046988:Proteasome Endopeptidase Complex; D009418:S100 Proteins; D010959:Tissue Plasminogen Activator; D025801:Ubiquitin; D000099248:S100 Calcium Binding Protein A10; C472822:ANXA2 protein, human