Abstract

Edg-1 was cloned as an novel immediate-early response gene induced following phorbol ester stimulation of human umbilical vein endothelial cell differentiation. The deduced amino acid sequence of the edg-1 protein suggest that it is a seven-pass transmembrane receptor. The edg-1 ligand is currently unknown and so edg-1 is classified as an orphan receptor. Edg-1 couples to the Gi family of polypeptides and initiates sustained activation the mitogen activated protein kinase pathway. Sustained activation of the MAP kinase pathway is required for cellular differentiation in PC-12 neuronal cells and morphologic differentiation in Dictyostelium. Edg-1 overexpression results in morphologic differentiation of HEK293 cells by suppressing cell-matrix adhesion, upregulating E- and P-cadherins and inducing cell-cell adhesion. These findings support the central hypothesis of this proposal which is that in vascular endothelial cells edg-1 signaling regulates the morphogenetic differentiation phase of the angiogenic response. The objective of this proposal is to define the signaling pathways involved in this morphogenetic differentiation, as well as definition of the phenotype of the edg-1-induced differentiated state.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045659-06
Application #
2770414
Study Section
Pathology A Study Section (PTHA)
Program Officer
Linder, Barbara
Project Start
1992-09-30
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

Thompson, Brian; Ancellin, Nicolas; Fernandez, Salvador M et al. (2006) Protein kinase Calpha and sphingosine 1-phosphate-dependent signaling in endothelial cell. Prostaglandins Other Lipid Mediat 80:15-27
Goligorsky, Michael S; Brodsky, Sergey V; Noiri, Eisei (2004) NO bioavailability, endothelial dysfunction, and acute renal failure: new insights into pathophysiology. Semin Nephrol 24:316-23
Ozaki, Harunobu; Hla, Timothy; Lee, Menq-Jer (2003) Sphingosine-1-phosphate signaling in endothelial activation. J Atheroscler Thromb 10:125-31
Ancellin, Nicolas; Colmont, Chantal; Su, Joseph et al. (2002) Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem 277:6667-75
Lee, M J; Thangada, S; Paik, J H et al. (2001) Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol Cell 8:693-704
Paik, J H; Chae Ss; Lee, M J et al. (2001) Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha vbeta3- and beta1-containing integrins. J Biol Chem 276:11830-7
Hla, T (2001) Sphingosine 1-phosphate receptors. Prostaglandins Other Lipid Mediat 64:135-42
Kluk, M J; Hla, T (2001) Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration. Circ Res 89:496-502
Hla, T; Lee, M J; Ancellin, N et al. (2001) Lysophospholipids--receptor revelations. Science 294:1875-8
Morales-Ruiz, M; Lee, M J; Zollner, S et al. (2001) Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. J Biol Chem 276:19672-7

Showing the most recent 10 out of 28 publications