Abstract
Growth factor receptors promote cell growth and survival by stimulating the activities of phosphatidylinositol 3-kinase and Akt/PKB. Here we report that Akt activation causes proteasomal degradation of substrates that control cell growth and survival. Expression of activated Akt triggered proteasome-dependent declines in the protein levels of the Akt substrates tuberin, FOXO1, and FOXO3a. The addition of proteasome inhibitors stabilized the phosphorylated forms of multiple Akt substrates, including tuberin and FOXO proteins. Activation of Akt triggered the ubiquitination of several proteins containing phosphorylated Akt substrate motifs. Together the data indicate that activated Akt stimulates proteasomal degradation of its substrates and suggest that Akt-dependent cell growth and survival are induced through the degradation of negative regulators of these processes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cysteine Endopeptidases / metabolism*
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DNA-Binding Proteins / metabolism*
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Interleukin-3 / pharmacology
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Mice
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Multienzyme Complexes / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Receptors, Interleukin-3 / metabolism
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Repressor Proteins / metabolism*
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Transcription Factors / metabolism*
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Transfection
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Ubiquitin / metabolism
Substances
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DNA-Binding Proteins
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Interleukin-3
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Multienzyme Complexes
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Proto-Oncogene Proteins
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Receptors, Interleukin-3
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Repressor Proteins
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Transcription Factors
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Ubiquitin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex