@article{2ca8ceb7de284654ac0195981341709d,
title = "pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner",
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.",
author = "Jianping Guo and Chakraborty, {Abhishek A.} and Pengda Liu and Wenjian Gan and Xingnan Zheng and Hiroyuki Inuzuka and Bin Wang and Jinfang Zhang and Linli Zhang and Min Yuan and Jesse Novak and Cheng, {Jin Q.} and Alex Toker and Sabina Signoretti and Qing Zhang and Asara, {John M.} and Kaelin, {William G.} and Wenyi Wei",
note = "Funding Information: We thank B. North, L. Wan, and other Wei laboratory members for critical reading of the manuscript; W. Yu for his critical help in providing the triple mutant form of VHL to analyze the critical amino acids in proline-hydroxylation binding pocket of VHL that mediates its interaction with hydroxylated Akt1; as well as members of Kaelin, Zhang, Toker, and Cheng laboratories for helpful discussions. J.G. is an NRSA T32 trainee and supported by 5T32HL007893-17. W.W. is an ACS research scholar. This work was supported in part by NIH grants (W.W., GM094777; W.W. and A.T., CA177910; and J.A., 1S10OD010612, 5P01CA120964, and 5P30CA006516).",
year = "2016",
month = aug,
day = "26",
doi = "10.1126/science.aad5755",
language = "English (US)",
volume = "353",
pages = "929--932",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6302",
}