Sprouty2 Protein Regulates Hypoxia-inducible Factor-? (HIF?) Protein Levels and Transcription of HIF?-responsive Genes.

ABSTRACT: The ?-subunits of hypoxia-inducible factors (HIF1? and HIF2?) promote transcription of genes that regulate glycolysis and cell survival and growth. Sprouty2 (Spry2) is a modulator of receptor tyrosine kinase signaling and inhibits cell proliferation by a number of different mechanisms. Because of the seemingly opposite actions of HIF? subunits and Spry2 on cellular processes, we investigated whether Spry2 regulates the levels of HIF1? and HIF2? proteins. In cell lines from different types of tumors in which the decreased protein levels of Spry2 have been associated with poor prognosis, silencing of Spry2 elevated HIF1? protein levels. Increases in HIF1? and HIF2? protein levels due to silencing of Spry2 also up-regulated HIF? target genes. Using HIF1? as a prototype, we show that Spry2 decreases HIF1? stability and enhances the ubiquitylation of HIF1? by a von Hippel-Lindau protein (pVHL)-dependent mechanism. Spry2 also exists in a complex with HIF1?. Because Spry2 can also associate with pVHL, using a mutant form of Spry2 (3P/3A-Spry2) that binds HIF1?, but not pVHL, we show that WT-Spry2, but not the 3P/3A-Spry2 decreases HIF1? protein levels. In accordance, expression of WT-Spry2, but not 3P/3A-Spry2 results in a decrease in HIF1?-sensitive glucose uptake. Together our data suggest that Spry2 acts as a scaffold to bring more pVHL/associated E3 ligase in proximity of HIF1? and increase its ubiquitylation and degradation. This represents a novel action for Spry2 in modulating biological processes regulated by HIF? subunits.

SUBMITTER: Hicks KC 

PROVIDER: S-EPMC4974391 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature