The E3 Ligase TRAF6 Regulates Akt Ubiquitination and Activation

By Wei-Lei Yang, Jing Wang, Chia-Hsin Chan, Szu-Wei Lee, Alejandro D. Campos, L. Hur, Brian C. Grabiner, Xin Lin, B. Darnay, Hui-Kuan Lin. Science, 2009

636 citations recorded by the source corpus.

Regulating Akt The protein kinase Akt is activated in response to receptor-activated generation of the signaling second messenger phosphatidylinositol 3,4,5-trisphosphate and has roles in regulation of diverse processes from metabolism and cell survival to transcription and tumorigenesis. Yang et al. (p. 1134; see the Perspective by Restuccia and Hemmings) report a previously unrecognized mode of regulation of Akt: covalent modification of Akt by linkage to lysine 63 of ubiquitin molecules. Such ubiquitination of Akt promotes localization to the cell membrane and consequent activation in cells stimulated with growth factors. TRAF6 (TNF receptor–associated factor 6) was implicated as the E3 ubiquitin ligase that mediates ubiquitination of Akt. Ubiquitination of Akt may influence its role in cancer cells: A mutant form of Akt associated with human cancer showed increased ubiquitination, and depletion of TRAF6 decreased tumorigenicity of a prostate cancer cell line in a mouse cancer model. Localization and activation of signaling proteins in cancer cells are controlled by ubiquitin labeling. 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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e318d7b1084826de6a94c9043c58256a6f43e8bc

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Citations in the corpus

The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “The cancerassociated AKT mutation displays an increasing trend in AKT ubiquitination.(175) In addition, SKP2 is also the E3 ligase for ErbBreceptor-mediated AKT ubiquitination.”
Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy (2020, background): “Notably, TRAF6 directly ubiquitinates Akt and inhibits its activity [57].”
A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles (2011, background): “Ubiquitylation of AKT1, a critical component in this pathway, is known to be important for its activation (49).”
The nuts and bolts of AGC protein kinases (2010, background): “It has also been reported that Lys63-linked ubiquitylation of Akt by the TNF receptor-associated factor 6 (TRAF6) E3 ligase facilitates its recruitment to the plasma membran”