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Review
. 2012 May;22(5):257-65.
doi: 10.1016/j.tcb.2012.02.003. Epub 2012 Mar 5.

Non-canonical Notch signaling: emerging role and mechanism

Peter Andersen  1 , Hideki Uosaki, Lincoln T Shenje, Chulan Kwon
Affiliations
Review

Non-canonical Notch signaling: emerging role and mechanism

Peter Andersen et al. Trends Cell Biol. 2012 May.

Abstract

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.

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Figures

Figure 1
Figure 1
Post-Translational Regulation of β-Catenin Protein by Notch. Notch can negatively regulate active β-catenin levels in a non-canonical fashion. In the presence of Wnts, membrane-bound Notch forms a complex with active β-catenin and degrades active β-catenin through an endo-lysosomal pathway. The degradation is independent of GSK3β-dependent destruction complex. Whether Notch is recycled back to the membrane is unclear. NICD can also regulate active β-catenin levels in a similar mechanism, but it is unknown whether endogenously processed NICD regulates active β-catenin protein. Protein interactions can be either direct or indirect.
Figure 2
Figure 2
Proposed Model for Numb Regulation of Notch and β-Catenin Numb may bind directly to Notch independent of α-adaptin (a) or may bind via an α-adaptin-dependent mechanism (b) with subsequent targeting of the Numb-Notch complex for lysosomal degradation. In both cases it may be possible that activated β-catenin could also be targeted for lysosomal destruction either as an innocent bystander or through an active process with unknown partners. Downregulation of Notch may occur through Numb-mediated targeting via ubiquitination intermediaries, such as E3-ligase, for proteasome-mediated degradation (c).
Figure I
Figure I
Canonical vs. Non-Canonical Notch Signaling
Figure II
Figure II
Proposed Model for Numb Regulation of Notch and β-Catenin
See this image and copyright information in PMC

References

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