Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3
(2003) In Journal of Cell Biology 163(4). p.8-723- Abstract
The Notch and transforming growth factor-beta (TGF-beta) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-beta signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-beta signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-beta regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1... (More)
The Notch and transforming growth factor-beta (TGF-beta) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-beta signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-beta signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-beta regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1 (NICD) cooperated synergistically with Smad3, an intracellular transducer of TGF-beta signals, to induce the activation of synthetic promoters containing multimerized CSL- or Smad3-binding sites. NICD and Smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and Smad3 could be recruited to CSL-binding sites on DNA in the presence of CSL and NICD. These findings indicate that Notch and TGF-beta signals are integrated by direct protein-protein interactions between the signal-transducing intracellular elements from both pathways.
(Less)
- author
- Blokzijl, Andries ; Dahlqvist, Camilla ; Reissmann, Eva ; Falk, Anna LU ; Moliner, Annalena ; Lendahl, Urban and Ibáñez, Carlos F
- publishing date
- 2003-11-24
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Binding Sites/physiology, Cells, Cultured, Chick Embryo, DNA-Binding Proteins/metabolism, Homeodomain Proteins/metabolism, Protein Structure, Tertiary/physiology, Receptor Cross-Talk/physiology, Receptor, Notch1, Receptors, Cell Surface/metabolism, Signal Transduction/physiology, Smad3 Protein, Trans-Activators/metabolism, Transcription Factors, Transforming Growth Factor beta/metabolism, Up-Regulation/physiology
- in
- Journal of Cell Biology
- volume
- 163
- issue
- 4
- pages
- 6 pages
- publisher
- Rockefeller University Press
- external identifiers
-
- pmid:14638857
- scopus:0345166971
- ISSN
- 0021-9525
- DOI
- 10.1083/jcb.200305112
- language
- English
- LU publication?
- no
- id
- 747f5e85-e0ce-475c-aaac-2bce24f60d23
- date added to LUP
- 2021-08-10 14:00:50
- date last changed
- 2024-04-20 10:42:19
@article{747f5e85-e0ce-475c-aaac-2bce24f60d23,
abstract = {{<p>The Notch and transforming growth factor-beta (TGF-beta) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-beta signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-beta signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-beta regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1 (NICD) cooperated synergistically with Smad3, an intracellular transducer of TGF-beta signals, to induce the activation of synthetic promoters containing multimerized CSL- or Smad3-binding sites. NICD and Smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and Smad3 could be recruited to CSL-binding sites on DNA in the presence of CSL and NICD. These findings indicate that Notch and TGF-beta signals are integrated by direct protein-protein interactions between the signal-transducing intracellular elements from both pathways.</p>}},
author = {{Blokzijl, Andries and Dahlqvist, Camilla and Reissmann, Eva and Falk, Anna and Moliner, Annalena and Lendahl, Urban and Ibáñez, Carlos F}},
issn = {{0021-9525}},
keywords = {{Animals; Binding Sites/physiology; Cells, Cultured; Chick Embryo; DNA-Binding Proteins/metabolism; Homeodomain Proteins/metabolism; Protein Structure, Tertiary/physiology; Receptor Cross-Talk/physiology; Receptor, Notch1; Receptors, Cell Surface/metabolism; Signal Transduction/physiology; Smad3 Protein; Trans-Activators/metabolism; Transcription Factors; Transforming Growth Factor beta/metabolism; Up-Regulation/physiology}},
language = {{eng}},
month = {{11}},
number = {{4}},
pages = {{8--723}},
publisher = {{Rockefeller University Press}},
series = {{Journal of Cell Biology}},
title = {{Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3}},
url = {{https://lup.lub.lu.se/search/files/101078168/Cross_talk_between_the_Notch_.pdf}},
doi = {{10.1083/jcb.200305112}},
volume = {{163}},
year = {{2003}},
}