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PMID: 9311995 Published · ppublish English Journal Article

TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.

The EMBO journal ·Vol. 16 ·No. 17 ·1997-09-01 ·Pages 5353-62

Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P

Abstract

Smad family members are newly identified essential intracellular signalling components of the transforming growth factor-beta (TGF-beta) superfamily. Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals. Smad4 is distantly related to Smads 2 and 3, and forms a heteromeric complex with Smad2 after TGF-beta or activin stimulation. Here we show that Smad2 and Smad3 interacted with the kinase-deficient TGF-beta type I receptor (TbetaR)-I after it was phosphorylated by TbetaR-II kinase. TGF-beta1 induced phosphorylation of Smad2 and Smad3 in Mv1Lu mink lung epithelial cells. Smad4 was found to be constitutively phosphorylated in Mv1Lu cells, the phosphorylation level remaining unchanged upon TGF-beta1 stimulation. Similar results were obtained using HSC4 cells, which are also growth-inhibited by TGF-beta. Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells. In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3. Smads 2, 3 and 4 accumulated in the nucleus upon TGF-beta1 treatment in Mv1Lu cells, and showed a synergistic effect in a transcriptional reporter assay using the TGF-beta-inducible plasminogen activator inhibitor-1 promoter. Dominant-negative Smad3 inhibited the transcriptional synergistic response by Smad2 and Smad4. These data suggest that TGF-beta induces heteromeric complexes of Smads 2, 3 and 4, and their concomitant translocation to the nucleus, which is required for efficient TGF-beta signal transduction.

MeSH Terms
Activin Receptors, Type I Amino Acid Sequence Animals Antibody Specificity Biological Transport COS Cells Cell Nucleus/metabolism DNA-Binding Proteins/immunology,metabolism Epithelial Cells Genes, Reporter Humans Lung/cytology Mink Models, Biological Molecular Sequence Data Phosphorylation Protein Binding Protein Serine-Threonine Kinases/metabolism Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/metabolism Signal Transduction Smad2 Protein Smad3 Protein Smad4 Protein Trans-Activators/immunology,metabolism Transcription, Genetic Tumor Cells, Cultured
Chemicals
DNA-Binding Proteins Receptors, Transforming Growth Factor beta SMAD2 protein, human SMAD3 protein, human SMAD4 protein, human Smad2 Protein Smad3 Protein Smad4 Protein Trans-Activators Protein Serine-Threonine Kinases Activin Receptors, Type I Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Nakao A
Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden.
Imamura T
Souchelnytskyi S
Kawabata M
Ishisaki A
Oeda E
Tamaki K
Hanai J
Heldin C H
Miyazono K
ten Dijke P
References (31)
31 references, click to expand
  1. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts.
    J Biol Chem. 1984 Sep 10;259(17):10995-1000 PMID: 6088525
  2. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.
    Nature. 1996 Sep 12;383(6596):168-72 PMID: 8774881
  3. Biological effects and binding properties of transforming growth factor-beta on human oral squamous cell carcinoma cells.
    Exp Cell Res. 1990 Apr;187(2):263-9 PMID: 2156718
  4. Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor.
    Cell. 1993 Nov 19;75(4):681-92 PMID: 8242743
  5. Characterization of type I receptors for transforming growth factor-beta and activin.
    Science. 1994 Apr 1;264(5155):101-4 PMID: 8140412
  6. Mechanism of activation of the TGF-beta receptor.
    Nature. 1994 Aug 4;370(6488):341-7 PMID: 8047140
  7. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster.
    Genetics. 1995 Mar;139(3):1347-58 PMID: 7768443
  8. Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects.
    J Cell Biol. 1995 Jul;130(1):217-26 PMID: 7790373
  9. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.
    Science. 1995 Dec 22;270(5244):2008-11 PMID: 8533096
  10. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
    Science. 1996 Jan 19;271(5247):350-3 PMID: 8553070
  11. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components.
    Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):790-4 PMID: 8570636
  12. Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily.
    Cell. 1996 May 17;85(4):479-87 PMID: 8653784
  13. MADR1, a MAD-related protein that functions in BMP2 signaling pathways.
    Cell. 1996 May 17;85(4):489-500 PMID: 8653785
  14. A human Mad protein acting as a BMP-regulated transcriptional activator.
    Nature. 1996 Jun 13;381(6583):620-3 PMID: 8637600
  15. Mad-related genes in the human.
    Nat Genet. 1996 Jul;13(3):347-9 PMID: 8673135
  16. TGFbeta signaling: receptors, transducers, and Mad proteins.
    Cell. 1996 Jun 28;85(7):947-50 PMID: 8674122
  17. Serine phosphorylation, chromosomal localization, and transforming growth factor-beta signal transduction by human bsp-1.
    J Biol Chem. 1996 Jul 26;271(30):17617-20 PMID: 8663601
  18. Xenopus mothers against decapentaplegic is an embryonic ventralizing agent that acts downstream of the BMP-2/4 receptor.
    Development. 1996 Aug;122(8):2359-66 PMID: 8756281
  19. A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.
    Genes Dev. 1996 Aug 1;10(15):1880-9 PMID: 8756346
  20. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.
    Cell. 1996 Aug 23;86(4):543-52 PMID: 8752209
  21. Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors.
    Curr Opin Cell Biol. 1996 Apr;8(2):139-45 PMID: 8791413
  22. Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth.
    Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8940-4 PMID: 8799132
  23. Nomenclature: vertebrate mediators of TGFbeta family signals.
    Cell. 1996 Oct 18;87(2):173 PMID: 8861901
  24. A transcriptional partner for MAD proteins in TGF-beta signalling.
    Nature. 1996 Oct 24;383(6602):691-6 PMID: 8878477
  25. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways.
    Nature. 1996 Oct 31;383(6603):832-6 PMID: 8893010
  26. Serine/threonine kinase receptors: mediators of transforming growth factor beta family signals.
    Cancer Surv. 1996;27:41-64 PMID: 8909794
  27. MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling.
    Cell. 1996 Dec 27;87(7):1215-24 PMID: 8980228
  28. Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway.
    J Biol Chem. 1997 Jan 31;272(5):2896-900 PMID: 9006934
  29. The C-terminal domain of Mad-like signal transducers is sufficient for biological activity in the Xenopus embryo and transcriptional activation.
    Mech Dev. 1997 Jan;61(1-2):127-40 PMID: 9076683
  30. DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells.
    Oncogene. 1997 Apr 24;14(16):1891-9 PMID: 9150356
  31. The antigenic index: a novel algorithm for predicting antigenic determinants.
    Comput Appl Biosci. 1988 Mar;4(1):181-6 PMID: 2454713
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.17.5353
Published
1997-09-01
Pages
5353-62
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170167
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/16.17.5353 PMC Full Text View journal details
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