TGF-β signaling (blue) requires Notch cooperation.

Cells exist in complicated environments filled with reinforcing and conflicting signals. Three recent papers (Blokzijl et al., page 723; Takizawa et al., 2003. Nucl. Acids. Res. 31:5723–5731; Dahlqvist et al., 2003. Development. 10.1242/dev.00834) describe a link between pathways downstream of two of the most important of these signals: Notch and the TGF-β/BMP systems.

Both signaling pathways trigger the release of initially receptor-localized species—the Notch intracellular domain (NICD) and the Smads, respectively—that then enter the nucleus. And recent microarray results suggested that both pathways converge on at least one common target gene. Now, Blokzijl et al. demonstrate that Notch and Smad3 (a protein released from the transforming growth factor β (TGF-β) receptor after ligand binding) bind each other, and then bind and activate a target promoter. The other two papers describe a similar association between Notch and Smad1 (which is downstream of the bone morphogenetic protein [BMP] receptor) that is enhanced by binding of coactivators (Takizawa et al.) and required for a BMP4-mediated block of muscle differentiation (Dahlqvist et al.).

Such a requirement for two signals could be seen as further reducing the choices available for developmental processes, which use and reuse a limited number of signaling pathways. But senior author Carlos Ibáñez sees the new complexes as the cell's equivalent of a computational AND gate, and anticipates that a closer investigation of signaling complexes will show that the complexes work like small microprocessors. Only with such integration, he says, can cells deal with all the complexity that surrounds them. ▪