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
2002 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, no 36, 11000-11007 p.Article in journal (Refereed) Published
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.
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
IdentifiersURN: urn:nbn:se:uu:diva-10420DOI: 10.1021/bi025936uPubMedID: 12206672OAI: oai:DiVA.org:uu-10420DiVA: diva2:38188