Sprouty2 Regulates Hypoxia Inducible Factor-alpha (HIFalpha) Protein Levels and Transcription of HIFalpha - Responsive Genes Journal Article

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Authors: Hicks, K. C.; Patel, T. B.
Article Title: Sprouty2 Regulates Hypoxia Inducible Factor-alpha (HIFalpha) Protein Levels and Transcription of HIFalpha - Responsive Genes
Abstract: The alpha-subunits of hypoxia inducible factors (HIF1alpha and HIF2alpha) 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 HIFalpha subunits and Spry2 on cellular processes, we investigated whether Spry2 regulates the levels of HIF1alpha and HIF2alpha 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 HIF1alpha protein levels. Increases in HIF1alpha and HIF2alpha protein levels due to silencing of Spry2 also upregulated HIFalpha target genes. Using HIF1alpha as a prototype, we show that Spry2 decreases HIF1alpha stability and enhances the ubiquitylation of HIF1alpha by a pVHL dependent mechanism. Spry2 also exists in a complex with HIF1alpha. Since Spry2 can also associate with pVHL, using a mutant form of Spry2 (3P/3A-Spry2) that binds HIF1alpha, but not pVHL, we show that WT-Spry2, but not the 3P/3A-Spry2 decreases HIF1alpha protein levels. In accordance, expression of WT-Spry2, but not 3P/3A-Spry2 results in a decrease in HIF1alpha-sensitive glucose uptake. Together our data suggest that Spry2 acts as a scaffold to bring more pVHL/associated E3 ligase in proximity of HIF1alpha and increase its ubiquitylation and degradation. This represents a novel action for Spry2 in modulating biological processes regulated by HIFalpha subunits.
Journal Title: The Journal of biological chemistry
ISSN: 1083-351X; 0021-9258
Publisher: The American Society for Biochemistry and Molecular Biology  
Date Published: 2016
Language: ENG
DOI/URL:

jbc.M116.714139
Notes: LR: 20160609; CI: Copyright (c) 2016; JID: 2985121R; OTO: NOTNLM; 2016/01/08 [received]; 2016/06/08 [accepted]; aheadofprint