Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3.
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.
Blokzijl
Andries
A
Department of Neuroscience, Karoliska Institute, 17177 Stockholm, Sweden.
Dahlqvist
Camilla
C
Reissmann
Eva
E
Falk
Anna
A
Moliner
Annalena
A
Lendahl
Urban
U
Ibáñez
Carlos F
CF
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta