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Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University.
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2002 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 36, 11000-11007 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2002. Vol. 41, no 36, 11000-11007 p.
Keyword [en]
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology, Adenosine Triphosphate/antagonists & inhibitors/*metabolism, Amino Acid Sequence, Animals, Antennapedia Homeodomain Protein, Binding Sites/drug effects, COS Cells, Cell Line, DNA-Binding Proteins/metabolism/pharmacology, Enzyme Inhibitors/pharmacology, Homeodomain Proteins/pharmacology, Imidazoles/pharmacology, Mink, Molecular Mimicry, Molecular Sequence Data, Molecular Weight, Nuclear Proteins, Peptide Fragments/chemical synthesis/pharmacology, Protein-Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism, Pyridines/pharmacology, Receptors; Transforming Growth Factor beta/*antagonists & inhibitors/metabolism, Recombinant Fusion Proteins/chemical synthesis/pharmacology, Signal Transduction/drug effects, Smad2 Protein, Smad3 Protein, Substrate Specificity, Trans-Activators/metabolism/pharmacology, Transcription Factors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism/*physiology
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10420DOI: 10.1021/bi025936uPubMedID: 12206672OAI: oai:DiVA.org:uu-10420DiVA: diva2:38188
Available from: 2007-03-22 Created: 2007-03-22 Last updated: 2017-12-11Bibliographically approved

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Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12206672&dopt=Citation

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Yakymovych, IhorEngström, UllaHeldin, Carl-HenrikSouchelnytskyi, Serhiy

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