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Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Microbiology and Immunology, Tohoku University of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Department of Microbiology and Immunology, Tohoku University of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2001 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 20, no 15, 4132-4142 p.Article in journal (Refereed) Published
Abstract [en]

Inhibitory Smads, i.e. Smad6 and Smad7, are potent antagonists of the BMP-Smad pathway by interacting with activated bone morphogenetic protein (BMP) type I receptors and thereby preventing the activation of receptor-regulated Smads, or by competing with activated R-Smads for heteromeric complex formation with Smad4. The molecular mechanisms that underlie the regulation of I-Smad activity have remained elusive. Here we report the identification of a cytoplasmic protein, previously termed associated molecule with the SH3 domain of STAM (AMSH), as a direct binding partner for Smad6. AMSH interacts with Smad6, but not with R- and Co-Smads, upon BMP receptor activation in cultured cells. Consistent with this finding, stimulation of cells with BMP induces a co-localization of Smad6 with AMSH in the cytoplasm. Ectopic expression of AMSH prolongs BMP-induced Smad1 phosphorylation, and potentiates BMP-induced activation of transcriptional reporter activity, growth arrest and apoptosis. The data strongly suggest that the molecular mechanism by which AMSH exerts its action is by inhibiting the binding of Smad6 to activated type I receptors or activated R-Smads.

Place, publisher, year, edition, pages
The European Molecular Biology Organization , 2001. Vol. 20, no 15, 4132-4142 p.
Keyword [en]
AMSH, BMP, signaling, Smad, TGF-β
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90979DOI: 10.1093/emboj/20.15.4132PubMedID: 11483516OAI: oai:DiVA.org:uu-90979DiVA: diva2:163527
Available from: 2003-10-20 Created: 2003-10-20 Last updated: 2010-05-25Bibliographically approved
In thesis
1. Regulation of TGF-β/Smad Signaling Through Smad Interacting Proteins
Open this publication in new window or tab >>Regulation of TGF-β/Smad Signaling Through Smad Interacting Proteins
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor-β (TGF-β) superfamily members are multi-functional regulators of cell fate. These factors signal by binding to a limited number of highly conserved transmembrane type I and type II serine/threonine kinase receptors. These receptors initiate signals into the cell via the Smad proteins. Up to date, 8 different mammalian Smads are reported and are divided into three subgroups; receptor regulated Smads (R-Smads), common mediator Smads (Co-Smads) and inhibitory Smads (I-Smads). This thesis investigates the function and regulation of TGF-β/Smad signaling through identification and characterization of Smad interacting proteins.

I-Smads, i.e. Smad6 and Smad7, are potent antagonists of the TGF-β superfamily signaling. We found that Smad7, but not Smad6, inhibits TGF-β1-induced growth inhibition and expression of immediate early response genes. Interestingly, in the absence of ligand, Smad7 was found to be predominantly localized in the nucleus, whereas Smad7 accumulated in the cytoplasm upon TGF-β receptor activation. Moreover, we found that the MH2 domain is important for nuclear export.

To investigate further the role of inhibitory Smads, we have identified AMSH as a Smad6 interacting protein using a yeast two-hybrid screening method. AMSH was previously discovered as the associated molecule with the SH3 domain of STAM. AMSH interacts with I-Smads, but not with R- and Co-Smads upon receptor activation and potentiates BMP-induced activation of transcriptional reporter activity, growth arrest and apoptosis. AMSH was found to prevent Smad6 from binding to activated type I receptors and/or activated R-Smads. Smad anchor for receptor activation (SARA) is critical for Smad2 and Smad3 activation by TGF-β receptors. The present studies show that the localization of SARA in early endosomes is regulated through its FYVE domain. We have found that the FYVE domain of SARA is sufficient and necessary for the early endosomal localization, probably through its interaction with PtdIns(3)P. Moreover, the localization of SARA in early endosomes is required for efficient TGF-β/Smad signaling.

Both Notch and BMP signaling pathways are important for vascular development. We have found that Herp2, which is originally known as one of the Notch target genes, is synergistically induced upon activation of Notch and BMP signaling pathways in endothelial cells (ECs). The critical elements for synergistical activation of Herp2 gene by BMP and Notch pathway were identified. Furthermore, the Notch intracellular domain interacts with Smad5 upon BMP receptor and this interaction becomes stronger in the presence of pCAF. Interestingly, Herp2 was found to antagonize BMP receptor- or Id-mediated EC migration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 55 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1296
Keyword
Cell and molecular biology, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-3690 (URN)91-554-5772-X (ISBN)
Public defence
2003-11-10, C8:301, BMC, Uppsala, 09:15
Opponent
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Available from: 2003-10-20 Created: 2003-10-20Bibliographically approved

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