title: 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.
abstract: 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.
authors.affiliation: Department of Medicine, University of Chicago, IL, USA. robert.doebele@ucdenver.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Frank T
authors.initials: FT
authors.lastname: Schulze-Hoepfner
authors.forename: Jia
authors.initials: J
authors.lastname: Hong
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chlenski
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Zeitlin
authors.forename: Kushboo
authors.initials: K
authors.lastname: Goel
authors.forename: Suzana
authors.initials: S
authors.lastname: Gomes
authors.forename: Yuru
authors.initials: Y
authors.lastname: Liu
authors.forename: Mark K
authors.initials: MK
authors.lastname: Abe
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nor
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.forename: Marsha Rich
authors.initials: MR
authors.lastname: Rosner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019699:Thrombospondins / Q000378:metabolism*; D014162:Transfection; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; C116122:RAPGEF3 protein, human; D019699:Thrombospondins; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human; D020827:rap1 GTP-Binding Proteins