Non-canonical activation of Notch signaling/target genes in vertebrates

Abstract

Evolutionarily conserved Notch signaling orchestrates diverse physiological mechanisms during metazoan development and homeostasis. Classically, ligand-activated Notch receptors transduce the signaling cascade through the interaction of DNA-bound CBF1-co-repressor complex. However, recent reports have demonstrated execution of a CBF1-independent Notch pathway through signaling cross-talks in various cells/tissues. Here, we have tried to congregate the reports that describe the non-canonical/CBF1-independent Notch signaling and target gene activation in vertebrates with specific emphasis on their functional relevance.

Fig. 1

Schematic of canonical Notch signaling: Canonical Notch signaling is activated by its ligand leading to γ-secretase cleavage of Notch intracellular domain (NICD) which in turn translocates into the nucleus. There, it converts the transcriptional co-repressor complex into an activator complex by recruiting MAML and specific co-activators (Co-A) following displacement of the co-repressor complex (including NCoR, HDAC and Co-R). Subsequently, the specific co-activator complex will trigger the transcription of Notch target genes (Hes/Herp family)

Fig. 2

Schematic of non-canonical Notch signaling/target gene activation. a The non-canonical Notch signaling (Type-I) pathway requires ligand mediated cleavage of Notch receptor but transduces the signals independent of CBF1 interaction. Here, the cleaved NICD interacts with tissue-specific co-activators (Co-A) and other undefined factors to activate downstream targets/functions. The cleaved NICD can also interact with components of other signaling pathways and activate downstream components of Notch signaling. b Non-canonical Notch target gene activation (Type-II) is completely devoid of either ligand-mediated NICD-release or CBF1-interaction, and hence target genes are activated through alternate signaling mechanisms. Downstream effectors of JNK, Shh and Wnt are known to directly activate the expression of Hes-1/Hairy-1 independent of Notch/CBF1 interaction. c Classification of Notch signaling and its functional implication. References for each signaling pathway are given in square brackets