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J. Biol. Chem., Vol. 282, Issue 27, 19781-19787, July 6, 2007

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Anthrax Edema Toxin Inhibits Endothelial Cell Chemotaxis via Epac and Rap1^*

Jia Hong¹, Robert C. Doebele^¶12, Mark W. Lingen^||, Lawrence A. Quilliam^**, Wei-Jen Tang, and Marsha Rich Rosner³

From the Ben May Department for Cancer Research, Departments of Neurobiology, Pharmacology, and Physiology, ^¶Medicine, and ^||Pathology, University of Chicago, Chicago, Illinois 60637 and the ^**Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, Indiana 46202

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.

Received for publication, January 5, 2007 , and in revised form, May 9, 2007.

^* This work was supported by National Institutes of Health (NIH) Grants CA109278 and CA112310 (to M. R. R.), a gift from the Cornelius Crane Trust for Eczema Research (to M. R. R.), NIH Training Grant HL-07605 in respiratory biology (to J. H.), NIH Grants GM53459 and GM62548 (to W.-J. T.) and CA108647 (to L. A. Q.), and NCI, National Institutes of Health Basic Research Training Grant CA09566 in medical oncology (to R. C. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Genentech fellow in hematology/oncology at the University of Chicago.

³ To whom correspondence should be addressed: Ben May Dept. for Cancer Research, Gordon Ctr. for Integrative Science, 929 E. 57th St., Chicago, IL 60637. Tel.: 773-702-0380; Fax: 1-773-702-4634; E-mail: m-rosner{at}uchicago.edu.

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