Non-canonical Notch signaling: emerging role and mechanism

Notch is an ancient transmembrane receptor with crucial roles in cell-fate choices. Although the ‘canonical’ Notch pathway and its core members are well established – involving ligand-induced cleavage of Notch for transcriptional regulation – it has been unclear whether Notch can also function independently of ligand and transcription (‘non-canonically’) through a common mechanism. Recent studies suggest that Notch can non-canonically exert its biological functions by post-translationally targeting Wnt/β-catenin signaling, an important cellular and developmental regulator. The non-canonical Notch pathway appears to be highly conserved from flies to mammals. Here, we discuss the emerging conserved mechanism and role of ligand/transcription-independent Notch signaling in cell and developmental biology.