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Published 24 November 2003. doi:10.1083/jcb.200305112
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© The Rockefeller University Press, 0021-9525/2003/11/723 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 723-728

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Cross-talk between the Notch and TGF-ß signaling pathways mediated by interaction of the Notch intracellular domain with Smad3



Andries Blokzijl1, Camilla Dahlqvist2, Eva Reissmann1, Anna Falk2, Annalena Moliner1, Urban Lendahl2 and Carlos F. Ibáñez1

1 Division of Molecular Neurobiology, Department of Neuroscience
2 Department of Cellular and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden

Address correspondence to Carlos F. Ibáñez, Dept. of Neuroscience, Karoliska Institute, Retzius v, 17177 Stockholm, Sweden. Tel.: 46-8-524-876-60. Fax: 46-8-33-95-48. email: carlos.ibanez{at}neuro.ki.se

The Notch and transforming growth factor-ß (TGF-ß) 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-ß signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-ß 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-ß 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-ß 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-ß signals are integrated by direct protein–protein interactions between the signal-transducing intracellular elements from both pathways.

Key Words: Hes-1; C2C12; CSL; Smad4; neural stem cell

A. Blokzijl and C. Dahlqvist contributed equally to this paper.

Abbreviations used in this paper: E, embryonic day; NICD, Notch intracellular domain.


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