title: Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells.
abstract: Cellular antioxidant enzymes play crucial roles in aerobic organisms by eliminating detrimental oxidants and maintaining the intracellular redox homeostasis. Therefore, the function of antioxidant enzymes is inextricably linked to the redox-dependent activities of multiple proteins and signaling pathways. Here, we report that the VEGFR2 RTK has an oxidation-sensitive cysteine residue whose reduced state is preserved specifically by peroxiredoxin II (PrxII) in vascular endothelial cells. In the absence of PrxII, the cellular H(2)O(2) level is markedly increased and the VEGFR2 becomes inactive, no longer responding to VEGF stimulation. Such VEGFR2 inactivation is due to the formation of intramolecular disulfide linkage between Cys1199 and Cys1206 in the C-terminal tail. Interestingly, the PrxII-mediated VEGFR2 protection is achieved by association of two proteins in the caveolae. Furthermore, PrxII deficiency suppresses tumor angiogenesis in vivo. This study thus demonstrates a physiological function of PrxII as the residential antioxidant safeguard specific to the redox-sensitive VEGFR2.
authors.affiliation: Division of Life and Pharmaceutical Science, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 127-750, Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.forename: Doo Jae
authors.initials: DJ
authors.lastname: Lee
authors.forename: Kyung Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Park
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Koh
authors.forename: Gou-Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta / Q000166:cytology / Q000201:enzymology*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000473:pathology; D021941:Caveolae / Q000201:enzymology; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004220:Disulfides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D040301:Vascular Endothelial Growth Factor Receptor-2; D003545:Cysteine