DEVELOPMENT A Notch in Smad Signaling

Blokzijl et al. demonstrated synergism between Notch and transforming growth factor-β (TGF-β) signaling pathways that depended on direct interactions between the Notch1 intracellular domain (NICD) and the TGF-β effector Smad3. Although Notch and TGF-β pathways both regulate cell fate during development, they have generally been believed to function independently. Both pathways mediate signaling from the plasma membrane to the cell nucleus; Notch signaling depends on the proteolytic release of the NICD, and TGF-β signaling depends on relocation of Smads. Noting that components of the Notch pathway are transcriptionally induced by TGF-β, Blokzijl et al. expressed a constitutively active TGF-β receptor in embryonic chick pericardial mesoderm and brain, and they observed ectopic expression of the Notch target c-hairy (a homolog of mammalian Hes-1). Mouse adult neural stem cells and C2C12 mouse myoblasts exposed to TGF-β showed a rapid increase in Hes-1 expression that did not require protein translation, which suggests direct activation of the Hes-1 gene. C2C12 cells expressing a dominant-negative mutation of CSL [C promoter-binding factor1/RBP-J, Su(H), and Lag-1, a DNA binding component of the Notch pathway], which blocks Notch signaling, did not respond to TGF-β with increased Hes-1. In C2C12 myoblasts overexpressing NICD, TGF-β stimulated expression of a gene reporter containing sequences from the Hes-1 promoter. The authors used a fusion protein containing full-length Smad3 to show Smad3-NICD binding in vitro and coimmunoprecipitation to demonstrate association in cells. Moreover, Smad3 was recruited to CSL-DNA binding sites in a cell-free system when CSL and NICD were both present. Thus, these two developmental pathways can act cooperatively through direct protein-protein interactions between NICD and Smad3.

A. Blokzijl, C. Dahlqvist, E. Reissmann, A. Falk, A. Moliner, U. Lendahl, C. F. Ibáñez, Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J. Cell Biol. 163, 723-728 (2003). [Abstract] [Full Text]