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Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-beta-dependent signaling but affects Smad7-dependent transcriptional activation
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, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2001 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 17, 14344-14349 p.Article in journal (Refereed) Published
Abstract [en]

Smad proteins are major components in the intracellular signaling pathway of transforming growth factor-beta (TGF-beta), and phosphorylation is an important mechanism in regulation of their functions. Smad7 was identified as a potent inhibitor of TGF-beta-dependent signaling. We have identified serine 249 in Smad7 as a major phosphorylation site, the phosphorylation of which was not affected by TGF-beta1. Abrogation of the phosphorylation by substitution of Ser-249 with alanine or aspartic acid residues did not affect the ability of Smad7 to inhibit TGF-beta1 and BMP7 signaling. No differences were found in the stability or in the intracellular distribution of Smad7 mutants compared with the wild-type molecule. However, Smad7 fused to the DNA-binding domain of GAL4 induced transcription from a reporter with mutated TATA minimal promoter in a Ser-249-dependent manner. Moreover, a reporter with the SV40 minimal promoter was inhibited by GAL4-Smad7, and this effect was also dependent on Ser-249 phosphorylation. The amplitude of effects on transcriptional regulation was dependent on cell type. Our results suggest that phosphorylation of Smad7, unlike phosphorylation of the receptor-regulated Smads, does not regulate TGF-beta signaling but rather affects TGF-beta-independent effects of Smad7 on transcriptional regulation.

Place, publisher, year, edition, pages
2001. Vol. 276, no 17, 14344-14349 p.
Keyword [en]
3T3 Cells, Amino Acid Sequence, Animals, Aspartic Acid/chemistry, Bone Morphogenetic Proteins/metabolism, COS Cells, Cell Nucleus/metabolism, DNA/metabolism, DNA-Binding Proteins/genetics/*metabolism/*physiology, Genes; Reporter, Ligands, Luciferases/metabolism, Mice, Microscopy; Fluorescence, Molecular Sequence Data, Mutation, Phosphorylation, Promoter Regions (Genetics), Protein Structure; Tertiary, Research Support; Non-U.S. Gov't, Serine/chemistry, Signal Transduction, Time Factors, Trans-Activation (Genetics), Trans-Activators/genetics/*metabolism/*physiology, Transcription; Genetic, Transfection, Transforming Growth Factor beta/*metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-73358DOI: 10.1074/jbc.M011019200PubMedID: 11278814OAI: oai:DiVA.org:uu-73358DiVA: diva2:101268
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2013-11-06Bibliographically approved

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Landström, MaréneHeldin, Carl-HenrikSouchelnytskyi, Serhiy

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