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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. J Biol Chem 2013 Apr 12;288(15):10265-74

Date

02/09/2013

Pubmed ID

23393131

Pubmed Central ID

PMC3624410

DOI

10.1074/jbc.M112.413542

Scopus ID

2-s2.0-84876229992   12 Citations

Abstract

The 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 (Verma, A., Bhattacharya, R., Remadevi, I., Li, K., Pramanik, K., Samant, G. V., Horswill, M., Chun, C. Z., Zhao, B., Wang, E., Miao, R. Q., Mukhopadhyay, D., Ramchandran, R., and Wilkinson, G. A. (2010) Blood 115, 4614-4622) showed that loss of ECSCR in primary ECs reduced tyrosine phosphorylation of vascular endothelial growth factor (VEGF) receptor 2/kinase insert domain receptor (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.

Author List

Kilari S, Remadevi I, Zhao B, Pan J, Miao R, Ramchandran R, North PE, You M, Rahimi N, Wilkinson GA

Authors

Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Jing Pan PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Cell Line
Endosomes
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases
Female
Hemangioma
Human Umbilical Vein Endothelial Cells
Humans
Indoles
Male
Membrane Proteins
Placenta
Pregnancy
Protein Kinase Inhibitors
Proteolysis
Proto-Oncogene Proteins c-akt
Pyrroles
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Zebrafish
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d