Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1.
Angiogenesis involves the assembly of endothelial cells into capillaries from a pre-existing vasculature. Because abnormal angiogenesis is a hallmark of many cancers, it is critical to find factors that control this process. Endothelial cells are enriched in the anthrax receptor; we therefore determined the effect of anthrax edema toxin (ET), an adenylyl cyclase, on chemotaxis. cAMP generated by ET does not block proliferation or survival but causes cytoskeletal changes and inhibits chemotaxis by primary human microvascular endothelial cells (HMVECs). These effects are due to the action of a downstream cAMP effector, Epac, a guanine nucleotide exchange-activating protein for Rap1 (RAP1-GEF). ET induces transcription of Epac-related activators of Rap1, Epac2 (RapGEF4), and MR-GEF/RapGEF5. Similar to ET, activated Epac or Rap1 induces cytoskeletal changes and blocks chemotaxis in human endothelial cells. These results identify Epac and Rap1 as key regulators of signaling cascades leading to endothelial cell chemotaxis.
Hong
Jia
J
Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Doebele
Robert C
RC
Lingen
Mark W
MW
Quilliam
Lawrence A
LA
Tang
Wei-Jen
WJ
Rosner
Marsha Rich
MR
D000262:Adenylyl Cyclases / Q000494:pharmacology*; D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000494:pharmacology*; D001427:Bacterial Toxins; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018000:Receptors, Peptide / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000187:drug effects; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; C417242:RAPGEF5 protein, human; D018000:Receptors, Peptide; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C030325:anthrax toxin; C070309:anthrax toxin receptors; D020663:ras Guanine Nucleotide Exchange Factors; D000242:Cyclic AMP; D000262:Adenylyl Cyclases