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.
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.
Doebele
Robert C
RC
Department of Medicine, University of Chicago, IL, USA. robert.doebele@ucdenver.edu
Schulze-Hoepfner
Frank T
FT
Hong
Jia
J
Chlenski
Alexandre
A
Zeitlin
Benjamin D
BD
Goel
Kushboo
K
Gomes
Suzana
S
Liu
Yuru
Y
Abe
Mark K
MK
Nor
Jacques E
JE
Lingen
Mark W
MW
Rosner
Marsha Rich
MR
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*
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