Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 325 (5944): 1134-1138

Copyright © 2009 by the American Association for the Advancement of Science

The E3 Ligase TRAF6 Regulates Akt Ubiquitination and Activation

Wei-Lei Yang,1,2 Jing Wang,1 Chia-Hsin Chan,1 Szu-Wei Lee,1,2 Alejandro D. Campos,3 Betty Lamothe,3 Lana Hur,3 Brian C. Grabiner,1,2 Xin Lin,1,2 Bryant G. Darnay,3 Hui-Kuan Lin1,2,*

Abstract: Akt signaling plays a central role in many biological functions, such as cell proliferation and apoptosis. Because Akt (also known as protein kinase B) resides primarily in the cytosol, it is not known how these signaling molecules are recruited to the plasma membrane and subsequently activated by growth factor stimuli. We found that the protein kinase Akt undergoes lysine-63 chain ubiquitination, which is important for Akt membrane localization and phosphorylation. TRAF6 was found to be a direct E3 ligase for Akt and was essential for Akt ubiquitination, membrane recruitment, and phosphorylation upon growth-factor stimulation. The human cancer-associated Akt mutant displayed an increase in Akt ubiquitination, in turn contributing to the enhancement of Akt membrane localization and phosphorylation. Thus, Akt ubiquitination is an important step for oncogenic Akt activation.

1 Department of Molecular and Cellular Oncology, The University of Texas M. D. 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 Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Functional Role of Asparaginyl Endopeptidase Ubiquitination by TRAF6 in Tumor Invasion and Metastasis.
Y. Lin, Y. Qiu, C. Xu, Q. Liu, B. Peng, G. F. Kaufmann, X. Chen, B. Lan, C. Wei, D. Lu, et al. (2014)
J Natl Cancer Inst 106, dju012
   Abstract »    Full Text »    PDF »
Distinct roles of TRAF6 at early and late stages of muscle pathology in the mdx model of Duchenne muscular dystrophy.
S. M. Hindi, S. Sato, Y. Choi, and A. Kumar (2014)
Hum. Mol. Genet. 23, 1492-1505
   Abstract »    Full Text »    PDF »
The CUL7/F-box and WD Repeat Domain Containing 8 (CUL7/Fbxw8) Ubiquitin Ligase Promotes Degradation of Hematopoietic Progenitor Kinase 1.
H. Wang, Y. Chen, P. Lin, L. Li, G. Zhou, G. Liu, C. Logsdon, J. Jin, J. L. Abbruzzese, T.-H. Tan, et al. (2014)
J. Biol. Chem. 289, 4009-4017
   Abstract »    Full Text »    PDF »
Regulation of Akt Signaling by Sirtuins: Its Implication in Cardiac Hypertrophy and Aging.
V. B. Pillai, N. R. Sundaresan, and M. P. Gupta (2014)
Circ. Res. 114, 368-378
   Abstract »    Full Text »    PDF »
TRAF4 Is a Critical Molecule for Akt Activation in Lung Cancer.
W. Li, C. Peng, M.-H. Lee, D. Lim, F. Zhu, Y. Fu, G. Yang, Y. Sheng, L. Xiao, X. Dong, et al. (2013)
Cancer Res. 73, 6938-6950
   Abstract »    Full Text »    PDF »
Glaucocalyxin A, a negative Akt regulator, specifically induces apoptosis in human brain glioblastoma U87MG cells.
X. Xiao, W. Cao, X. Jiang, W. Zhang, Y. Zhang, B. Liu, J. Cheng, H. Huang, J. Huo, and X. Zhang (2013)
Acta Biochim Biophys Sin 45, 946-952
   Abstract »    Full Text »    PDF »
Akt SUMOylation Regulates Cell Proliferation and Tumorigenesis.
R. Li, J. Wei, C. Jiang, D. Liu, L. Deng, K. Zhang, and P. Wang (2013)
Cancer Res. 73, 5742-5753
   Abstract »    Full Text »    PDF »
Toll-like receptor-mediated IRE1{alpha} activation as a therapeutic target for inflammatory arthritis.
Q. Qiu, Z. Zheng, L. Chang, Y.-S. Zhao, C. Tan, A. Dandekar, Z. Zhang, Z. Lin, M. Gui, X. Li, et al. (2013)
EMBO J. 32, 2477-2490
   Abstract »    Full Text »    PDF »
The Tomato Fni3 Lysine-63-Specific Ubiquitin-Conjugating Enzyme and Suv Ubiquitin E2 Variant Positively Regulate Plant Immunity.
R. V. Mural, Y. Liu, T. R. Rosebrock, J. J. Brady, S. Hamera, R. A. Connor, G. B. Martin, and L. Zeng (2013)
PLANT CELL 25, 3615-3631
   Abstract »    Full Text »    PDF »
TRAF6 Upregulates Expression of HIF-1{alpha} and Promotes Tumor Angiogenesis.
H. Sun, X.-B. Li, Y. Meng, L. Fan, M. Li, and J. Fang (2013)
Cancer Res. 73, 4950-4959
   Abstract »    Full Text »    PDF »
TNFR-Associated Factor 6 Regulates TCR Signaling via Interaction with and Modification of LAT Adapter.
J.-J. Xie, J.-Q. Liang, L.-H. Diao, A. Altman, and Y. Li (2013)
J. Immunol. 190, 4027-4036
   Abstract »    Full Text »    PDF »
SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization.
P. Yi, W. Xia, R.-C. Wu, D. M. Lonard, M.-C. Hung, and B. W. O'Malley (2013)
Genes & Dev. 27, 274-287
   Abstract »    Full Text »    PDF »
Ubiquitin-dependent Regulation of Phospho-AKT Dynamics by the Ubiquitin E3 Ligase, NEDD4-1, in the Insulin-like Growth Factor-1 Response.
C.-D. Fan, M. A. Lum, C. Xu, J. D. Black, and X. Wang (2013)
J. Biol. Chem. 288, 1674-1684
   Abstract »    Full Text »    PDF »
Posttranslational Modification and Quality Control.
X. Wang, J. S. Pattison, and H. Su (2013)
Circ. Res. 112, 367-381
   Abstract »    Full Text »    PDF »
The Akt DUBbed InAktive.
K. Lin (2013)
Science Signaling 6, pe1
   Abstract »    Full Text »    PDF »
Cycles of Ubiquitination and Deubiquitination Critically Regulate Growth Factor-Mediated Activation of Akt Signaling.
W.-L. Yang, G. Jin, C.-F. Li, Y. S. Jeong, A. Moten, D. Xu, Z. Feng, W. Chen, Z. Cai, B. Darnay, et al. (2013)
Science Signaling 6, ra3
   Abstract »    Full Text »    PDF »
TRIM Protein-Mediated Regulation of Inflammatory and Innate Immune Signaling and Its Association with Antiretroviral Activity.
P. D. Uchil, A. Hinz, S. Siegel, A. Coenen-Stass, T. Pertel, J. Luban, and W. Mothes (2013)
J. Virol. 87, 257-272
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGF{beta}-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection.
S. Gorjestani, B. G. Darnay, and X. Lin (2012)
J. Biol. Chem. 287, 44143-44150
   Abstract »    Full Text »    PDF »
Reciprocal Interaction between TRAF6 and Notch Signaling Regulates Adult Myofiber Regeneration upon Injury.
S. M. Hindi, P. K. Paul, S. Dahiya, V. Mishra, S. Bhatnagar, S. Kuang, Y. Choi, and A. Kumar (2012)
Mol. Cell. Biol. 32, 4833-4845
   Abstract »    Full Text »    PDF »
Sequestosome 1/p62, a Scaffolding Protein, Is a Newly Identified Partner of IRS-1 Protein.
T. Geetha, C. Zheng, N. Vishwaprakash, T. L. Broderick, and J. R. Babu (2012)
J. Biol. Chem. 287, 29672-29678
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor Receptor-associated Factor Family Protein 2 Is a Key Mediator of the Epidermal Growth Factor-induced Ribosomal S6 Kinase 2/cAMP-responsive Element-binding Protein/Fos Protein Signaling Pathway.
C. Peng, F. Zhu, W. Wen, K. Yao, S. Li, T. Zykova, K. Liu, X. Li, W.-Y. Ma, A. M. Bode, et al. (2012)
J. Biol. Chem. 287, 25881-25892
   Abstract »    Full Text »    PDF »
Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1.
J. Fang, G. Rhyasen, L. Bolanos, C. Rasch, M. Varney, M. Wunderlich, S. Goyama, G. Jansen, J. Cloos, C. Rigolino, et al. (2012)
Blood 120, 858-867
   Abstract »    Full Text »    PDF »
Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications.
S. Fulda, K. Rajalingam, and I. Dikic (2012)
EMBO Mol Med. 4, 545-556
   Abstract »    Full Text »    PDF »
TRAF6 Protein Couples Toll-like Receptor 4 Signaling to Src Family Kinase Activation and Opening of Paracellular Pathway in Human Lung Microvascular Endothelia.
A. Liu, P. Gong, S. W. Hyun, K. Z. Q. Wang, E. A. Cates, D. Perkins, D. D. Bannerman, A. C. Puche, V. Y. Toshchakov, S. Fang, et al. (2012)
J. Biol. Chem. 287, 16132-16145
   Abstract »    Full Text »    PDF »
The E3 Ubiquitin Ligase TRAF6 Intercedes in Starvation-Induced Skeletal Muscle Atrophy through Multiple Mechanisms.
P. K. Paul, S. Bhatnagar, V. Mishra, S. Srivastava, B. G. Darnay, Y. Choi, and A. Kumar (2012)
Mol. Cell. Biol. 32, 1248-1259
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome System Meets Angiogenesis.
N. Rahimi (2012)
Mol. Cancer Ther. 11, 538-548
   Abstract »    Full Text »    PDF »
Activation of Akt, Not Connexin 43 Protein Ubiquitination, Regulates Gap Junction Stability.
C. A. Dunn, V. Su, A. F. Lau, and P. D. Lampe (2012)
J. Biol. Chem. 287, 2600-2607
   Abstract »    Full Text »    PDF »
The mTOR (Mammalian Target of Rapamycin) Kinase Maintains Integrity of mTOR Complex 2.
C.-H. Chen and D. D. Sarbassov (2011)
J. Biol. Chem. 286, 40386-40394
   Abstract »    Full Text »    PDF »
The role of Skp2 in hematopoietic stem cell quiescence, pool size, and self-renewal.
J. Wang, F. Han, J. Wu, S.-W. Lee, C.-H. Chan, C.-Y. Wu, W.-L. Yang, Y. Gao, X. Zhang, Y. S. Jeong, et al. (2011)
Blood 118, 5429-5438
   Abstract »    Full Text »    PDF »
A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles.
S. A. Wagner, P. Beli, B. T. Weinert, M. L. Nielsen, J. Cox, M. Mann, and C. Choudhary (2011)
Mol. Cell. Proteomics 10, M111.013284
   Abstract »    Full Text »    PDF »
Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System.
S.-Y. Kim, J.-H. Lee, J. W. Huh, J. Y. Ro, Y.-M. Oh, S.-D. Lee, S. An, and Y.-S. Lee (2011)
J. Biol. Chem. 286, 31932-31943
   Abstract »    Full Text »    PDF »
Critical Role of Monoubiquitination of Histone H2AX Protein in Histone H2AX Phosphorylation and DNA Damage Response.
C.-Y. Wu, H.-Y. Kang, W.-L. Yang, J. Wu, Y. S. Jeong, J. Wang, C.-H. Chan, S.-W. Lee, X. Zhang, B. Lamothe, et al. (2011)
J. Biol. Chem. 286, 30806-30815
   Abstract »    Full Text »    PDF »
The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy.
N. R. Sundaresan, V. B. Pillai, D. Wolfgeher, S. Samant, P. Vasudevan, V. Parekh, H. Raghuraman, J. M. Cunningham, M. Gupta, and M. P. Gupta (2011)
Science Signaling 4, ra46
   Abstract »    Full Text »    PDF »
MicroRNA-146a Downregulates NF{kappa}B Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma.
J. H. Paik, J.-Y. Jang, Y. K. Jeon, W. Y. Kim, T. M. Kim, D. S. Heo, and C.-W. Kim (2011)
Clin. Cancer Res. 17, 4761-4771
   Abstract »    Full Text »    PDF »
mTOR Complex 2 Targets Akt for Proteasomal Degradation via Phosphorylation at the Hydrophobic Motif.
Y.-T. Wu, W. Ouyang, A. S. Lazorchak, D. Liu, H.-M. Shen, and B. Su (2011)
J. Biol. Chem. 286, 14190-14198
   Abstract »    Full Text »    PDF »
Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.
H. Jo, P.-K. Lo, Y. Li, F. Loison, S. Green, J. Wang, L. E. Silberstein, K. Ye, H. Chen, and H. R. Luo (2011)
PNAS 108, 6486-6491
   Abstract »    Full Text »    PDF »
Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response.
S. Gardam, V. M. Turner, H. Anderton, S. Limaye, A. Basten, F. Koentgen, D. L. Vaux, J. Silke, and R. Brink (2011)
Blood 117, 4041-4051
   Abstract »    Full Text »    PDF »
OX40 Complexes with Phosphoinositide 3-Kinase and Protein Kinase B (PKB) To Augment TCR-Dependent PKB Signaling.
T. So, H. Choi, and M. Croft (2011)
J. Immunol. 186, 3547-3555
   Abstract »    Full Text »    PDF »
Phosphorylation of Caspase-8 (Thr-263) by Ribosomal S6 Kinase 2 (RSK2) Mediates Caspase-8 Ubiquitination and Stability.
C. Peng, Y.-Y. Cho, F. Zhu, J. Zhang, W. Wen, Y. Xu, K. Yao, W.-Y. Ma, A. M. Bode, and Z. Dong (2011)
J. Biol. Chem. 286, 6946-6954
   Abstract »    Full Text »    PDF »
ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3{beta}-Mediated Phosphorylation of Rictor.
C.-H. Chen, T. Shaikenov, T. R. Peterson, R. Aimbetov, A. K. Bissenbaev, S.-W. Lee, J. Wu, H.-K. Lin, and D. D. Sarbassov (2011)
Science Signaling 4, ra10
   Abstract »    Full Text »    PDF »
Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice.
P. K. Paul, S. K. Gupta, S. Bhatnagar, S. K. Panguluri, B. G. Darnay, Y. Choi, and A. Kumar (2010)
J. Cell Biol. 191, 1395-1411
   Abstract »    Full Text »    PDF »
Ubiquitin, a novel paracrine messenger of cardiac cell survival.
D. Li and C. Depre (2010)
Cardiovasc Res 86, 1-3
   Full Text »    PDF »
Activated Rac1 GTPase Translocates Protein Phosphatase 5 to the Cell Membrane and Stimulates Phosphatase Activity in Vitro.
A. Chatterjee, L. Wang, D. L. Armstrong, and S. Rossie (2010)
J. Biol. Chem. 285, 3872-3882
   Abstract »    Full Text »    PDF »
2009: Signaling Breakthroughs of the Year.
E. M. Adler (2010)
Science Signaling 3, eg1
   Abstract »    Full Text »    PDF »
Lysine 63 Polyubiquitination in Immunotherapy and in Cancer-promoting Inflammation.
I. Martinez-Forero, A. Rouzaut, A. Palazon, J. Dubrot, and I. Melero (2009)
Clin. Cancer Res. 15, 6751-6757
   Abstract »    Full Text »    PDF »
Blocking Akt-ivity.
D. F. Restuccia and B. A. Hemmings (2009)
Science 325, 1083-1084
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882