Members of the Notch family of proteins are single-pass transmembrane receptors whose ligands are members of the Jagged and Delta-like families. Binding of Delta on the surface of a cell to Notch on the surface of an adjacent cell (a trans interaction) triggers the proteolytic processing of Notch; its intracellular domain is cleaved and translocates to the nucleus to activate target gene expression. Notch signaling is important in determining cell fate and in defining boundaries between neighboring cells during development. Binding of Delta to Notch on the same cell (a cis interaction) inhibits Notch signaling; however, how Notch integrates cis and trans signals is unclear. Sprinzak et al. used time-lapse microscopy and a fluorescence-based Notch reporter system to quantify the response of Notch to Delta molecules presented in either state. Delta presented in trans generated a graded response in Notch signaling. When presented in cis, Delta inhibited Notch signaling; however, titration of the amount of Delta resulted in a sharp Notch response. The authors developed a model that suggested that, when Delta is more abundant than Notch on the same cell, Notch signaling is blocked and the cell becomes a “sender” of signals, through Delta, to neighboring cells. When the relative protein abundance is reversed, however, the cell becomes a “receiver,” with Notch responding in a graded manner to Delta on an adjacent cell. The authors suggest that, through this switch mechanism, Notch-Delta signaling between adjacent cells is amplified, which helps to sharply define cell boundaries within a developing tissue.
D. Sprinzak, A. Lakhanpal, L. LeBon, L. A. Santat, M. E. Fontes, G. A. Anderson, J. Garcia-Ojalvo, M. B. Elowitz, Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465, 86–90 (2010). [PubMed]