Title | pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Guo J, Chakraborty AA, Liu P, Gan W, Zheng X, Inuzuka H, Wang B, Zhang J, Zhang L, Yuan M, Novak J, Cheng JQ, Toker A, Signoretti S, Zhang Q, Asara JM, Kaelin WG, Wei W |
Journal | Science |
Volume | 353 |
Issue | 6302 |
Pagination | 929-32 |
Date Published | 2016 08 26 |
ISSN | 1095-9203 |
Keywords | Cell Line, Tumor, Enzyme Activation, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Mutation, Neoplasms, Phosphorylation, Proline, Proto-Oncogene Proteins c-akt, Tumor Hypoxia, Tumor Microenvironment, Von Hippel-Lindau Tumor Suppressor Protein |
Abstract | Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance. |
DOI | 10.1126/science.aad5755 |
Alternate Journal | Science |
PubMed ID | 27563096 |
PubMed Central ID | PMC5326551 |
Grant List | R01 CA200651 / CA / NCI NIH HHS / United States R01 GM094777 / GM / NIGMS NIH HHS / United States K01 AG041218 / AG / NIA NIH HHS / United States P01 CA120964 / CA / NCI NIH HHS / United States R01 CA200573 / CA / NCI NIH HHS / United States T32 HL007893 / HL / NHLBI NIH HHS / United States K99 CA207867 / CA / NCI NIH HHS / United States R01 CA177910 / CA / NCI NIH HHS / United States R01 GM089763 / GM / NIGMS NIH HHS / United States S10 OD010612 / OD / NIH HHS / United States P30 CA006516 / CA / NCI NIH HHS / United States |
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