Abstract
The direct mechanism by which the serine/threonine kinase Akt (also known as protein kinase B (PKB)) regulates cell growth is unknown. Here, we report that Drosophila melanogaster Akt/PKB stimulates growth by phosphorylating the tuberous sclerosis complex 2 (Tsc2) tumour suppressor and inhibiting formation of a Tsc1-Tsc2 complex. We show that Akt/PKB directly phosphorylates Drosophila Tsc2 in vitro at the conserved residues, Ser 924 and Thr 1518. Mutation of these sites renders Tsc2 insensitive to Akt/PKB signalling, increasing the stability of the Tsc1-Tsc2 complex within the cell. Stimulating Akt/PKB signalling in vivo markedly increases cell growth/size, disrupts the Tsc1-Tsc2 complex and disturbs the distinct subcellular localization of Tsc1 and Tsc2. Furthermore, all Akt/PKB growth signals are blocked by expression of a Tsc2 mutant lacking Akt phosphorylation sites. Thus, Tsc2 seems to be the critical target of Akt in mediating growth signals for the insulin signalling pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Cell Division
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics
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Drosophila melanogaster / growth & development
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Drosophila melanogaster / metabolism
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Eye / growth & development
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Humans
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In Vitro Techniques
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Insulin / metabolism
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Models, Biological
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Mutagenesis, Site-Directed
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Subcellular Fractions / metabolism
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
Substances
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Drosophila Proteins
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Insulin
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Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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TSC1 protein, human
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TSC2 protein, human
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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AKT1 protein, human
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Akt1 protein, Drosophila
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt