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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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HEK293 Cells
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HeLa Cells
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Humans
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Mice
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Mutation
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Phosphorylation / genetics
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Plasmids
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Phosphatase 2 / metabolism
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Proto-Oncogene Proteins c-akt* / chemistry
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Proto-Oncogene Proteins c-akt* / genetics
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Proto-Oncogene Proteins c-akt* / metabolism
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Real-Time Polymerase Chain Reaction
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Serine / genetics
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Serine / metabolism*
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Signal Transduction / genetics*
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Threonine / genetics
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Threonine / metabolism*
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / genetics
Substances
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Carrier Proteins
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ST13 protein, human
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Tumor Suppressor Proteins
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Threonine
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Serine
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Ubiquitin-Protein Ligases
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Proto-Oncogene Proteins c-akt
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Protein Phosphatase 2
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Proteasome Endopeptidase Complex