Noncanonical Notch Signaling

Discovered nearly a century ago, today, Notch is known to mediate several biological processes through the canonical pathway that involves ligands, RBPJ, proteases, and coactivators. However, recent studies in vertebrates and invertebrates reveal that Notch can also exert its effect independent of RBPJ, in a noncanonical fashion. These studies demonstrate that Notch can exert its noncanonical role not only through nuclear partners but also via nonnuclear or cytosolic interactions. Additionally, there now is increasing evidence that Notch signaling can be initiated in a “noncanonical” fashion, independent of ligands. In this review, we detail the different cytosolic and nuclear, noncanonical interactions of Notch and discuss how they affect signaling processes in various contexts. We also discuss the evidence for ligand-independent, noncanonical initiation of Notch signaling.