Proline hydroxylation linked to Akt activation

Abstract

Oxygen-sensing enzymes regulate the Akt kinase 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 ).