Abstract
Transforming growth factor-beta (TGFbeta) is a potent regulator of cell proliferation, differentiation, apoptosis, and migration. TGF-beta type I receptor (TbetaR-I), which has intrinsic serine/threonine kinase activity, is a key component in activation of intracellular TGFbeta signaling. We studied two different classes of TbetaR-I inhibitors, i.e., compounds interfering with the ATP-binding site of the kinase and substrate-mimicking peptides. We found that pyridinylimidazole compounds inhibited TbetaR-I kinase at micromolar concentration. A representative compound, SB203580, inhibited in vivo Smad2 phosphorylation by TbetaR-I and affected TGFbeta-dependent transcriptional activation. Peptides mimicking the TbetaR-I phosphorylation sites at the C-terminus of Smad2 also inhibited the autophosphorylation of TbetaR-I and phosphorylation of Smad2 by TbetaR-I in vitro and in vivo, whereas a similar peptide from Smad5 was without effect. The substrate-mimicking peptide, fused to penetratin, inhibited a TGFbeta1-dependent transcriptional response in a luciferase reporter assay and ligand-dependent growth inhibition of Mv1Lu cells. Thus, the substrate-mimetic peptide is a new type of specific inhibitor of the TGFbeta signaling in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Adenosine Triphosphate / antagonists & inhibitors
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Adenosine Triphosphate / metabolism*
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Amino Acid Sequence
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Animals
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Antennapedia Homeodomain Protein
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Binding Sites / drug effects
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COS Cells
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Cell Line
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / pharmacology
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Enzyme Inhibitors / pharmacology
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Homeodomain Proteins / pharmacology
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Imidazoles / pharmacology
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Mink
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Molecular Mimicry
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Molecular Sequence Data
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Molecular Weight
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Nuclear Proteins*
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Peptide Fragments / chemical synthesis
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Peptide Fragments / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / pharmacology
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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 / metabolism
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Recombinant Fusion Proteins / chemical synthesis
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction* / drug effects
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Smad2 Protein
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Smad3 Protein
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Substrate Specificity
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Trans-Activators / metabolism
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Trans-Activators / pharmacology
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Transcription Factors*
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / physiology*
Substances
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Antennapedia Homeodomain Protein
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DNA-Binding Proteins
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Enzyme Inhibitors
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Homeodomain Proteins
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Imidazoles
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Nuclear Proteins
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Peptide Fragments
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Pyridines
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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Smad2 Protein
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Smad3 Protein
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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SB 203580