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

Blood. 2009 Nov 12;114(20):4592-600. doi: 10.1182/blood-2009-04-217042. Epub 2009 Aug 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Endothelial Cells / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Inhibitor of Differentiation Protein 1 / metabolism
  • MAP Kinase Kinase 5 / metabolism*
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Neovascularization, Pathologic / metabolism*
  • Signal Transduction / physiology
  • Thrombospondins / metabolism*
  • Transfection
  • rap1 GTP-Binding Proteins / metabolism*


  • Guanine Nucleotide Exchange Factors
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • RAPGEF3 protein, human
  • Thrombospondins
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase 5
  • MAP2K5 protein, human
  • rap1 GTP-Binding Proteins