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PMID:10077593

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Citation

Moser, TL, Stack, MS, Asplin, I, Enghild, JJ, Højrup, P, Everitt, L, Hubchak, S, Schnaper, HW and Pizzo, SV (1999) Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 96:2811-6

Abstract

Angiostatin, a proteolytic fragment of plasminogen, is a potent antagonist of angiogenesis and an inhibitor of endothelial cell migration and proliferation. To determine whether the mechanism by which angiostatin inhibits endothelial cell migration and/or proliferation involves binding to cell surface plasminogen receptors, we isolated the binding proteins for plasminogen and angiostatin from human umbilical vein endothelial cells. Binding studies demonstrated that plasminogen and angiostatin bound in a concentration-dependent, saturable manner. Plasminogen binding was unaffected by a 100-fold molar excess of angiostatin, indicating the presence of a distinct angiostatin binding site. This finding was confirmed by ligand blot analysis of isolated human umbilical vein endothelial cell plasma membrane fractions, which demonstrated that plasminogen bound to a 44-kDa protein, whereas angiostatin bound to a 55-kDa species. Amino-terminal sequencing coupled with peptide mass fingerprinting and immunologic analyses identified the plasminogen binding protein as annexin II and the angiostatin binding protein as the alpha/beta-subunits of ATP synthase. The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis. Angiostatin also bound to the recombinant alpha-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen. Angiostatin's antiproliferative effect on endothelial cells was inhibited by as much as 90% in the presence of anti-alpha-subunit ATP synthase antibody. Binding of angiostatin to the alpha/beta-subunits of ATP synthase on the cell surface may mediate its antiangiogenic effects and the down-regulation of endothelial cell proliferation and migration.

Links

PubMed PMC15851

Keywords

Adenosine Triphosphatases/metabolism; Angiostatins; Antineoplastic Agents/metabolism; Antineoplastic Agents/pharmacology; Cell Division/drug effects; Cell Movement/drug effects; Cells, Cultured; Endothelium, Vascular/cytology; Endothelium, Vascular/metabolism; Humans; Membrane Proteins/metabolism; Neovascularization, Pathologic/prevention & control; Peptide Fragments/metabolism; Peptide Fragments/pharmacology; Plasminogen/metabolism; Plasminogen/pharmacology; Protein Binding

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PLMN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P06576

F

Seeded From UniProt

complete

HUMAN:PLMN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25705

F

Seeded From UniProt

complete

HUMAN:ATPB

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00747

F

Seeded From UniProt

complete

HUMAN:ATPB

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATPA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00747

F

Seeded From UniProt

complete

HUMAN:ATPA

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ATPA

involved_in

GO:0001937: negative regulation of endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ATPA

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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