The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
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.
Yang
Wei-Lei
WL
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Jing
J
Chan
Chia-Hsin
CH
Lee
Szu-Wei
SW
Campos
Alejandro D
AD
Lamothe
Betty
B
Hur
Lana
L
Grabiner
Brian C
BC
Lin
Xin
X
Darnay
Bryant G
BG
Lin
Hui-Kuan
HK
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
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