Document Detail


VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells.
MedLine Citation:
PMID:  23199280     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: The potential receptor for hydrogen sulfide (H2S) remains unknown.
RESULTS: H2S could directly activate vascular endothelial growth factor receptor 2 (VEGFR2) and that a small interfering RNA (siRNA)-mediated knockdown of VEGFR2 inhibited H2S-induced migration of human vascular endothelial cells. H2S promoted angiogenesis in Matrigel plug assay in mice and this effect was attenuated by a VEGF receptor inhibitor. Using tandem mass spectrometry (MS), we identified a new disulfide complex located between Cys1045 and Cys1024 within VEGFR2 that was labile to H2S-mediated modification. Kinase activity of the mutant VEGFR2 (C1045A) devoid of the Cys1045-Cys1024 disulfide bond was significantly higher than wild-type VEGFR2. Transfection with vectors expressing VEGFR2 (C1045A) caused a significant increase in cell migration, while the migration-promoting effect of H2S disappeared in the cells transfected with VEGFR2 (C1045A). Therefore, the Cys1045-Cys1024 disulfide bond serves as an intrinsic inhibitory motif and functions as a molecular switch for H2S. The formation of the Cys1045-Cys1024 disulfide bond disrupted the integrity of the active conformation of VEGFR2. Breaking the Cys1045-Cys1024 disulfide bond recovered the active conformation of VEGFR2. This motif was prone to a nucleophilic attack by H2S via an interaction of their frontier molecular orbitals. siRNA-mediated knockdown of cystathionine γ-lyase attenuated migration of vascular endothelial cells induced by VEGF or moderate hypoxia.
INNOVATION AND CONCLUSION: The study provides the first piece of evidence of a molecular switch in H2S-targeting receptor protein kinase in H2S-induced angiogenesis and that may be applicable to additional kinases containing functionally important disulfide bonds in mediating various H2S actions.
Authors:
Bei-Bei Tao; Shu-Yuan Liu; Cai-Cai Zhang; Wei Fu; Wen-Jie Cai; Yi Wang; Qing Shen; Ming-Jie Wang; Ying Chen; Li-Jia Zhang; Yi-Zhun Zhu; Yi-Chun Zhu
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-28
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  19     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-09     Completed Date:  2014-01-31     Revised Date:  2014-08-12    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  448-64     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cystathionine gamma-Lyase / genetics,  metabolism
Endothelial Cells / metabolism*
Female
Fluorescent Antibody Technique
Humans
Hydrogen Sulfide / metabolism*
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Molecular Dynamics Simulation
Mutation
Phosphatidylinositol 3-Kinases / genetics,  metabolism
Proto-Oncogene Proteins c-akt / genetics,  metabolism
RNA, Small Interfering
Reactive Oxygen Species / metabolism
Vascular Endothelial Growth Factor A / genetics,  metabolism
Vascular Endothelial Growth Factor Receptor-2 / chemistry,  genetics,  metabolism*
Chemical
Reg. No./Substance:
0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/Vascular Endothelial Growth Factor A; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 4.4.1.1/Cystathionine gamma-Lyase; YY9FVM7NSN/Hydrogen Sulfide
Comments/Corrections

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