Endothelial Cell-Specific Chemotaxis Receptor (ECSCR) enhances Vascular Endothelial Growth Factor (VEGF) Receptor-2/Kinase insert domain receptor (KDR) activation and promotes proteolysis of internalized KDR
- Authors
- Kilari, S., Remadevi, I., Zhao, B., Pan, J., Miao, R., Ramchandran, R., North, P.E., You, M., Rahimi, N., and Wilkinson, G.A.
- ID
- ZDB-PUB-130222-9
- Date
- 2013
- Source
- The Journal of biological chemistry 288(15): 10265-10274 (Journal)
- Registered Authors
- Ramchandran, Ramani
- Keywords
- angiogenesis, cell biology, endosomes, endothelial cell, vascular endothelial growth factor (VEGF)
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Line
- Endosomes/genetics
- Endosomes/metabolism
- Enzyme Activation/drug effects
- Enzyme Activation/physiology
- Extracellular Signal-Regulated MAP Kinases/genetics
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Female
- Hemangioma/genetics
- Hemangioma/metabolism
- Hemangioma/pathology
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/metabolism*
- Humans
- Indoles/pharmacology
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Placenta/metabolism
- Placenta/pathology
- Pregnancy
- Protein Kinase Inhibitors/pharmacology
- Proteolysis*
- Proto-Oncogene Proteins c-akt
- Pyrroles/pharmacology
- Vascular Endothelial Growth Factor Receptor-1/genetics
- Vascular Endothelial Growth Factor Receptor-1/metabolism
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/metabolism*
- Zebrafish
- PubMed
- 23393131 Full text @ J. Biol. Chem.
Endothelial Cell-Specific Chemotaxis Receptor (ECSCR) is a cell-surface protein selectively expressed by endothelial cells (ECs), with roles in EC migration, apoptosis and proliferation. Our previous study (1) showed that loss of ECSCR in primary ECs reduced tyrosine phosphorylation of vascular endothelial growth factor (VEGF) receptor 2/KDR but not VEGF receptor 1/FLT1. Here we show that ECSCR biochemically associates with KDR, but not FLT1, and that the predicted ECSCR cytoplasmic and transmembrane regions can each confer association with KDR. Stimulation with VEGF165 rapidly and transiently increases ECSCR/KDR complex formation, a process blocked by the KDR tyrosine kinase inhibitor compound SU5416 or inhibitors of endosomal acidification. Triple labeling experiments show VEGF stimulated KDR+/ECSCR+ intracellular co-localization. Silencing of ECSCR disrupts VEGF-induced KDR activation and AKT and ERK phosphorylation, and impairs VEGF-stimulated KDR degradation. In zebrafish, ecscr interacts with kdrl during intersomitic vessel sprouting. Human placenta and infantile hemangioma samples highly express ECSCR protein, suggesting a role for ECSCR-KDR interaction in these tissues.