PerspectiveCell Signaling

Proline hydroxylation linked to Akt activation

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Science  26 Aug 2016:
Vol. 353, Issue 6302, pp. 870-871
DOI: 10.1126/science.aah6254

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Prolyl hydroxylases are oxygen-sensing enzymes that regulate the abundance of hypoxia-inducible factors (HIF)1α and HIF2α, which control the cellular response to oxygen deprivation (hypoxia). Three prolyl hydroxylases target the HIFα molecules, EglN1 (PHD2), EglN2 (PHD1), and EglN3 (PHD3) (1). All three are widely expressed iron (Fe++) and α-ketoglutarate-dependent dioxygenases. When the oxygen tension is normal, they hydroxylate HIF1α and HIF2α. Hydroxylated HIFα molecules are recognized and ubiquitinated by an E3 ubiquitin ligase complex containing the von Hippel-Lindau tumor-suppressor protein pVHL (1), leading to their proteasomal degradation. Inactivation of prolyl hydroxylases during hypoxia results in the stabilization of HIFα molecules. On page 929 of this issue, Guo et al. present evidence that a prolyl hydroxylation-dependent pathway also plays an important role in the regulation of the Akt kinase, which in turn is a key player in oncogenesis (2).