<i>Cis-</i>activation in the Notch signaling pathway.

Abstract

The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (<i>cis</i>) and across cell boundaries (<i>trans</i>). Previous work has shown that <i>cis-</i>interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that <i>cis</i>-ligands can also activate Notch receptors. This <i>cis-</i>activation process resembles <i>trans-</i>activation in its ligand level dependence, susceptibility to <i>cis-</i>inhibition, and sensitivity to Fringe modification. <i>Cis-</i>activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how <i>cis-</i>activation could potentially expand the capabilities of Notch signaling, for example enabling 'negative' (repressive) signaling. These results establish <i>cis</i>-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.