TRAF6-mediated regulation of the PI3 kinase (PI3K)-Akt-GSK3beta cascade is required for TNF-induced cell survival.
We recently demonstrated that the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) helps maintenance of cell survival by regulating glycogen synthase kinase 3beta (GSK3beta) activity during TNF signaling. However, the molecular linkage between TRAF6 and GSK3beta signaling is unknown. Herein, we showed that TRAF6 positively regulated cell survival by modulating PI3K-Akt-GSK3beta cascades. In 3T3 cells lacking TRAF6, but not those lacking TRAF2, TNF stimulation led to prolonged hyperphosphorylation of Akt, which coincided with the activation of upstream PI3K. Pharmacologically blocking PI3K significantly inhibited Akt and GSK3beta phosphorylation. Importantly, PI3K inhibition rescued cell death in TRAF6-null 3T3 cells. These data suggested TRAF6 regulates TNF-mediated cell survival through PI3K-Akt-GSK3beta cascades.
Yoon
Kwiyeom
K
Division of Life and Pharmaceutical Sciences, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, 11-1, Daehyun-dong, Seoul 120-750, Republic of Korea.
Jung
Eun Joo
EJ
Lee
Soo Young
SY
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; C000605507:Gsk3b protein, mouse