Angiogenesis is a multi-step process requiring signals to induce endothelial cell proliferation, migration, and assembly. The Eph receptor tyrosine kinases (RTKs) and their ligands, ephrins, are important mediators of endothelial cell migration and attachment. As membrane tethered ligands, ephrins are capable of transmitting signals bi-directionally. Previous studies from our laboratory have shown that ephrin-B1 is activated by a soluble form of the EphB1-Fc receptor which lacks a cytoplasmic domain and thus is incapable of transmitting forward signals. In addition, soluble EphB1-Fc stimulation of endothelial cells induces cell migration, attachment, and in vivo angiogenesis. These cellular changes require the PDZ binding domain of ephrin B1. Based on these data, we hypothesize that (1) ephrin-B1 reverse signaling is mediated by PDZ adapter proteins through which downstream signaling pathways are activated, and (2) internalization of surface ephrin-B1 represents a mechanism by which ephrin-B1-mediated reverse signaling is regulated. To test these hypotheses, we propose to investigate signaling components downstream of ephrin-B1 by identifying ephrin B1 adapter proteins and pathways that transduce signals affecting endothelial cell migration and adhesion. We will also determine the role of ephrin-B1 internalization in regulating ehrin B1 activation and signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL074517-01
Application #
6691219
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Schucker, Beth
Project Start
2003-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$41,608
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Fang, Wei Bin; Brantley-Sieders, Dana M; Parker, Monica A et al. (2005) A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene 24:7859-68
Parker, Monica; Roberts, Richard; Enriquez, Miriam et al. (2004) Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated pathway. Biochem Biophys Res Commun 323:17-23
Brantley-Sieders, Dana; Parker, Monica; Chen, Jin (2004) Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des 10:3431-42