TRAF6-mediated regulation of the PI3 kinase (PI3K)-Akt-GSK3beta cascade is required for TNF-induced cell survival |
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Authors: | Yoon Kwiyeom Jung Eun Joo Lee Soo Young |
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Institution: | a 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 b Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea |
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Abstract: | We recently demonstrated that the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) helps maintenance of cell survival by regulating glycogen synthase kinase 3β (GSK3β) activity during TNF signaling. However, the molecular linkage between TRAF6 and GSK3β signaling is unknown. Herein, we showed that TRAF6 positively regulated cell survival by modulating PI3K-Akt-GSK3β 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 GSK3β phosphorylation. Importantly, PI3K inhibition rescued cell death in TRAF6-null 3T3 cells. These data suggested TRAF6 regulates TNF-mediated cell survival through PI3K-Akt-GSK3β cascades. |
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Keywords: | TNF TRAF6 Cell survival PI3 kinase Akt GSK3β |
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