title: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei-Lei
authors.initials: WL
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Campos
authors.forename: Betty
authors.initials: B
authors.lastname: Lamothe
authors.forename: Lana
authors.initials: L
authors.lastname: Hur
authors.forename: Brian C
authors.initials: BC
authors.lastname: Grabiner
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018129:Phosphatidylinositol Phosphates; D048029:TNF Receptor-Associated Factor 6; C060974:phosphatidylinositol 3,4,5-triphosphate; D007334:Insulin-Like Growth Factor I; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt