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 2O 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.
| Original language | English |
|---|---|
| Pages (from-to) | 545-558 |
| Number of pages | 14 |
| Journal | Molecular Cell |
| Volume | 44 |
| Issue number | 4 |
| DOIs | |
| State | Published - 18 Nov 2011 |
Bibliographical note
Funding Information:We thank Bert Vogelstein for adenoviral system, David Cheresh for VEGFR2-encoding constructs, and Sue Goo Rhee for sharing knockout mice. This study was supported by the 21C Frontier Functional Proteomics Project (FPR08-B1-190), a National Research Foundation of Korea grant (2011-0006244) funded by the Ministry of Education, Science, and Technology, and the GIST Systems Biology Infrastructure Establishment Grant (2011) through Ewha Research Center for Systems Biology. D.H.K., K.W.L., J.Y.L., and Y.S.P. are recipients of the Brain Korea 21 Grant.