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Blood, 12 November 2009, Vol. 114, No. 20, pp. 4592-4600. Prepublished online as a Blood First Edition Paper on August 26, 2009; DOI 10.1182/blood-2009-04-217042. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-04-217042v1 114/20/4592    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Doebele, R. C. Articles by Rosner, M. R. PubMed PubMed Citation Articles by Doebele, R. C. Articles by Rosner, M. R. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis Robert C. Doebele1,2, Frank T. Schulze-Hoepfner3, Jia Hong2, Alexandre Chlenski4, Benjamin D. Zeitlin5, Kushboo Goel1,2, Suzana Gomes2, Yuru Liu4, Mark K. Abe4, Jacques E. Nor5, Mark W. Lingen6, and Marsha Rich Rosner2 1 Department of Medicine and 2 Ben May Department for Cancer Research, University of Chicago, IL; 3 Department of Urology, Northwestern University, Chicago, IL; 4 Department of Pediatrics, University of Chicago, IL; 5 Department of Restorative Sciences, School of Dentistry, University of Michigan, Ann Arbor; and 6 Department of Pathology, University of Chicago, IL Tumors depend upon angiogenesis for growth and metastasis. It is therefore critical to understand the inhibitory signaling mechanisms in endothelial cells that control angiogenesis. Epac is a cyclic adenosine 5'-monophosphate–activated guanine nucleotide exchange factor for Rap1. In this study, we show that activation of Epac or Rap1 leads to potent inhibition of angiogenesis in vivo. Epac/Rap1 activation down-regulates inhibitor of differentiation 1 (Id1), which negatively regulates thrombospondin-1 (TSP1), an inhibitor of angiogenesis. Consistent with this mechanism, activation of Epac/Rap 1 induces expression of TSP1; conversely, depletion of Epac reduces TSP1 levels in endothelial cells. Blockade of TSP1 binding to its receptor, CD36, rescues inhibition of chemotaxis or angiogenesis by activated Epac/Rap1. Mitogen-activated protein kinase kinase 5, a downstream mediator of vascular endothelial growth factor, antagonizes the effects of Epac/Rap1 by inducing Id1 and suppressing TSP1 expression. Finally, TSP1 is also secreted by fibroblasts in response to Epac/Rap1 activation. These results identify Epac and Rap1 as inhibitory regulators of the angiogenic process, implicate Id1 and TSP1 as downstream mediators of Epac/Rap1, and highlight a novel interplay between pro- and antiangiogenic signaling cascades involving multiple cell types within the angiogenic microenvironment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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