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Sci. Signal., 8 January 2013
Vol. 6, Issue 257, p. ra3
[DOI: 10.1126/scisignal.2003197]

RESEARCH ARTICLES

Cycles of Ubiquitination and Deubiquitination Critically Regulate Growth Factor–Mediated Activation of Akt Signaling

Wei-Lei Yang1,2, Guoxiang Jin1, Chien-Feng Li3,4,5, Yun Seong Jeong1,2, Asad Moten1,6, Dazhi Xu1, Zizhen Feng1, Wei Chen1, Zhen Cai1, Bryant Darnay7, Wei Gu8, and Hui-Kuan Lin1,2*

1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
3 Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.
4 National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
5 Department of Biotechnology, Southern Taiwan University, Tainan 710, Taiwan.
6 Faculty of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA.
7 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8 Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.

Abstract: K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor–mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor–induced ubiquitination of Akt have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquitination of Akt and the function of Akt deubiquitination remain largely unclear. We showed that CYLD was a DUB for Akt and suppressed growth factor–mediated ubiquitination and activation of Akt. CYLD directly removed ubiquitin moieties from Akt under serum-starved conditions. CYLD dissociated from Akt upon growth factor stimulation, thereby allowing E3 ligases to induce ubiquitination and activation of Akt. CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake, and, when injected into mice, growth of prostate tumors. Our findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in determining its plasma membrane localization and activation—and further identify CYLD as a molecular switch for these processes.

* To whom correspondence should be addressed. E-mail: hklin{at}mdanderson.org

Citation: W.-L. Yang, G. Jin, C.-F. Li, Y. S. Jeong, A. Moten, D. Xu, Z. Feng, W. Chen, Z. Cai, B. Darnay, W. Gu, H.-K. Lin, Cycles of Ubiquitination and Deubiquitination Critically Regulate Growth Factor–Mediated Activation of Akt Signaling. Sci. Signal. 6, ra3 (2013).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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