@article{35740749508f42edad7ad8549c433933,
title = "SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis",
abstract = "The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.",
author = "Guihua Wang and Jie Long and Yuan Gao and Weina Zhang and Fei Han and Chuan Xu and Li Sun and Yang, {Shun Chin} and Jingqin Lan and Zhenlin Hou and Zhen Cai and Guoxiang Jin and Hsu, {Che Chia} and Wang, {Yu Hui} and Junbo Hu and Chen, {Tsai Yu} and Hongyu Li and Lee, {Min Gyu} and Lin, {Hui Kuan}",
note = "Funding Information: We are grateful to the members of Lin{\textquoteright}s lab for critical inputs and suggestions. We thank Z.-P. Liu, Y. Shinkai, F. J. Rauscher III, B. Vogelstein, D. Bohmann, M.C. Hung and R. Janknecht for providing mice, cell lines or plasmids. We thank E. Spooner for performing mass spectrometry assays. We acknowledge the support of Cellular Imaging & flow cytometry Shared of Resource, the Wake Forest Baptist Comprehensive Cancer Center, supported by the National Cancer Institute{\textquoteright}s Cancer Center Support Grant (P30CA012197). This work is supported by start-ups from Wake Forest School of Medicine, NIH grants (R01CA182424 and R01CA193813) to H.K.L., NIH grants (RO1CA194094 and RO1CA197178) to H.L. and NIH grants (R01CA207098 and R01CA207109) to M.G.L. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41556-018-0266-1",
language = "English (US)",
volume = "21",
pages = "214--225",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "2",
}