Srinivasan, SrimathiChitalia, VipulMeyer, Rosana D.Hartsough, EdwardMehta, ManishaHarrold, ItratAnderson, NicoleFeng, HuiSmith, LoisJiang, YanCostello, Catherine E.Rahimi, Nader2017-08-172015Srinivasan, Srimathi, Vipul Chitalia, Rosana D. Meyer, Edward Hartsough, Manisha Mehta, Itrat Harrold, Nicole Anderson, et al. 2015. Hypoxia-Induced Expression of Phosducin-Like 3 Regulates Expression of VEGFR-2 and Promotes Angiogenesis. Angiogenesis 18, no. 4: 449–462. doi:10.1007/s10456-015-9468-3.0969-6970http://nrs.harvard.edu/urn-3:HUL.InstRepos:33776185Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2.en-USangiogenesischaperone proteinhypoxian-terminal methionine acetylationPDCL3protein ubiquitinationVEGFR-2Journal Article2017-08-1710.1007/s10456-015-9468-3