title: 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.
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.
authors: Department of Pediatrics and Developmental Vascular Biology Program, Medical College of Wisconsin and Children's Research Institute, Milwaukee, Wisconsin 53226, USA.
authors: Sreenivasulu
authors: S
authors: Kilari
authors: Indulekha
authors: I
authors: Remadevi
authors: Baofeng
authors: B
authors: Zhao
authors: Jing
authors: J
authors: Pan
authors: Robert
authors: R
authors: Miao
authors: Ramani
authors: R
authors: Ramchandran
authors: Paula E
authors: PE
authors: North
authors: Ming
authors: M
authors: You
authors: Nader
authors: N
authors: Rahimi
authors: George A
authors: GA
authors: Wilkinson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006391:Hemangioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt; D011758:Pyrroles / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D051017:Apoptosis Regulatory Proteins; C531407:ECSCR protein, human; D007211:Indoles; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
references: Genes Cells. 2009 Mar;14(3):281-93
references: 19267780
references: Blood. 2007 Nov 15;110(10):3627-36
references: 17698971
references: Cardiovasc Pathol. 2006 Nov-Dec;15(6):303-17
references: 17113009
references: Blood. 2009 Jan 29;113(5):1192-9
references: 18723694
references: Infect Immun. 1984 Nov;46(2):448-52
references: 6500699
references: Toxicol Appl Pharmacol. 2008 May 1;228(3):301-14
references: 18358510
references: Cancer Metastasis Rev. 2013 Jun;32(1-2):77-82
references: 23229817
references: Dev Cell. 2005 Aug;9(2):197-207
references: 16054027
references: Curr Opin Cell Biol. 2012 Apr;24(2):188-93
references: 22366328
references: Nature. 2010 May 27;465(7297):483-6
references: 20445537
references: J Cell Biochem. 2002;85(2):357-68
references: 11948691
references: Cell. 1999 Jul 23;98(2):147-57
references: 10428027
references: Nat Med. 2008 Nov;14(11):1236-46
references: 18931684
references: Proc Natl Acad Sci U S A. 2009 May 19;106(20):8227-32
references: 19416853
references: Traffic. 2006 Sep;7(9):1270-82
references: 17004325
references: Blood. 2010 Jun 3;115(22):4614-22
references: 20086248
references: Biochim Biophys Acta. 2010 Mar;1804(3):567-80
references: 19761875
references: Genesis. 2000 Oct;28(2):75-81
references: 11064424
references: PLoS One. 2011;6(6):e21482
references: 21720547
references: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9472-7
references: 21593423
references: J Biol Chem. 2000 Jun 2;275(22):16986-92
references: 10747927
references: J Cell Sci. 2012 Jan 15;125(Pt 2):265-75
references: 22357968
references: J Lipid Res. 2009 Aug;50(8):1641-52
references: 19366995
references: J Biol Chem. 2003 May 30;278(22):20091-7
references: 12649282
references: Circ Res. 2008 Sep 26;103(7):710-6
references: 18757825
references: Cell Signal. 2012 Sep;24(9):1810-20
references: 22617029
references: Arch Dermatol. 2001 May;137(5):559-70
references: 11346333
references: Hum Reprod. 1996 May;11(5):1090-8
references: 8671397
references: Cardiovasc Res. 2011 Feb 15;89(3):604-13
references: 21088116
references: Sci Signal. 2011 May 03;4(171):pe24
references: 21540453
references: Nature. 2010 May 27;465(7297):487-91
references: 20445540
references: J Biol Chem. 2008 Sep 12;283(37):25110-25114
references: 18628209
references: J Biol Chem. 2007 Aug 17;282(33):24049-56
references: 17575273
references: Blood. 2006 Oct 15;108(8):2624-31
references: 16638931
references: J Cell Sci. 2009 Sep 15;122(Pt 18):3385-92
references: 19706677
references: BMC Genomics. 2008 Apr 07;9:153
references: 18394197
references: Blood. 2011 Jul 21;118(3):816-26
references: 21586748
references: EMBO J. 2005 Jul 6;24(13):2342-53
references: 15962004
references: Arterioscler Thromb Vasc Biol. 2008 Sep;28(9):1640-6
references: 18556573