Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase |
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Authors: | Chih-Hao SuCheng-Yi Wang Keng-Hsin LanChung-Pin Li Yee ChaoHan-Chieh Lin Shou-Dong LeeWei-Ping Lee |
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Affiliation: | a Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwanb Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwanc Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwand Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan |
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Abstract: | Phosphorylation at Thr308 and Ser473 is known to activate Akt, a major kinase in mammalian cells. Once activated to turn on downstream signaling pathways, Akt returns to an inactive pool via PP2A-mediated dephosphorylation. We show here that Thr308 and Ser473 phosphorylations prompt Akt to enter the CHIP-mediated ubiquitin-proteasome pathway. Mutation at either Thr308 or Ser473 dampened its ability to bind to the U-box E3 ligase CHIP (C-terminal Hsp70 -interacting protein), and the Akt mutants revealed decreased rate of ubiquitination by CHIP. Our study unveils that the well-known phosphorylations responsible for Akt activation turn out to transduce recognition signals for Akt-CHIP binding and ensuing degradation. |
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Keywords: | Akt Hsp90 CHIP Proteasome |
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