The E3 Ligase TRAF6 Regulates Akt Ubiquitination and Activation

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.