Abstract
Insulin-like growth factor-I inhibits transforming growth factor-beta (TGF-beta) signaling by blocking activation of Smad3 (S3), via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway. Here we provide the first report that the kinase activity of Akt is necessary for its ability to suppress many TGF-beta responses, including S3 activation and induction of apoptosis. Wild-type and myristoylated Akts (Akt(WT) and Akt(Myr)) suppress TGF-beta-induced phospho-activation of S3 but not Smad2 (S2), whereas kinase-dead Akt1 (Akt1K179M) or dominant-negative PI3K enhances TGF-beta-induced phospho-activation of both S2 and S3. Using siRNA, rapamycin (Rap), and adenoviral expression for FKBP12-resistant and constitutively active TGF-beta type I receptor (ALK5), we demonstrate that mammalian target of Rap (mTOR) mediates Akt1 suppression of phospho-activation of S3. These and further data on Akt1-S3 binding do not support a recently proposed model that Akt blocks S3 activation through physical interaction and sequestration of S3 from TGF-beta receptors. We propose a novel model whereby Akt suppresses activation of S3 in an Akt kinase-dependent manner through mTOR, a likely route for loss of tumor suppression by TGF-beta in cancers.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors*
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Activin Receptors, Type I / genetics
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Activin Receptors, Type I / metabolism
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Animals
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Apoptosis
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Cells, Cultured
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Humans
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Mutation
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-akt / physiology*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Rats
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Sirolimus / pharmacology
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Smad2 Protein / metabolism
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Smad3 Protein / metabolism*
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TOR Serine-Threonine Kinases
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Tacrolimus Binding Protein 1A / metabolism
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / metabolism
Substances
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RNA, Small Interfering
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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Protein Kinases
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MTOR protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, rat
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Tacrolimus Binding Protein 1A
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Sirolimus