%0 Journal Article %J Angiogenesis %D 2015 %T Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. %A Srinivasan, Srimathi %A Chitalia, Vipul %A Meyer, Rosana D %A Hartsough, Edward %A Mehta, Manisha %A Harrold, Itrat %A Anderson, Nicole %A Feng, Hui %A Smith, Lois E H %A Jiang, Yan %A Costello, Catherine E %A Rahimi, Nader %X

Expression 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.

%B Angiogenesis %V 18 %P 449-62 %8 2015 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26059764?dopt=Abstract %R 10.1007/s10456-015-9468-3