Similar Mechanisms Regulated by γ-Secretase are Involved in Both Directions of the Bi-Directional Notch-Delta Signaling Pathway as well as Play a Potential Role in Signaling Events Involving Type 1 Transmembrane Proteins

Abstract

In the canonical Notch signaling pathway, intramembrane cleavage by gamma-secretase serves to release an intracellular domain of Notch that has activity in the nucleus through binding to transcription factors. In addition, we showed that Notch also supplies signals to Delta, a major Notch ligand, to release the intracellular domain of Delta by gamma-secretase from the cell membrane, which then translocates to the nucleus, where it mediates the transcription of specific genes. Therefore, the Notch-Delta signaling pathway is bi-directional and similar mechanisms regulated by gamma-secretase are involved in both directions. Recently, it was demonstrated that many type 1 transmembrane proteins including Notch, Delta and amyloid precursor protein (APP) are substrates for gamma-secretase and release intracellular domains of these proteins from cell membranes. These observations that the common enzyme, gamma-secretase, modulates proteolysis and the turnover of possible signaling molecules have led to the attractive hypothesis that mechanisms similar to the Notch-Delta signaling pathway may widely contribute to gamma-secretase-regulated signaling pathways, including APP signaling which leads to Alzheimer's disease. Here, we review the molecular mechanisms of the Notch-Delta signaling pathway in a bi-directional manner, and discuss the recent progress in understanding the biology of gamma-secretase-regulated signaling with respect to neurodegeneration.

Neuroinflammation on the Epigenetics of Neural Stem Cells

“…Notch signaling is a conserved pathway from insects to mammals, which contributes to cell-to-cell communication (Louvi and Artavanis-Tsakonas, 2006) and controls cell fate determination in the CNS (Lundkvist and Lendahl, 2001). Upon Notch activation by its ligand, the Notch intracellular domain (NICD) is released from the plasma membrane and is translocated into the nucleus, where it converts a particular repressor complex into an activator complex (Nakayama et al, 2008). It is confirmed that Notch ligands are indeed expressed in neuronally committed NPCs and young neurons, and that these ligands activate Notch signaling in the residual NSCs.…”

Epigenetic mechanism in sequential differentiation of neural stem cells

“…29 Upon ligand binding, the intracellular domain of Notch (NICD) is released from the plasma membrane and translocates into the nucleus, where it converts the CBF1(RBP-J)/Su(H)/LAG1 (CSL) repressor complex into an activator complex. 30,31 The best characterized target genes for Notch signaling are hairy/enhancer of split (hes) genes, which are members of the bHLH family. 32 The products of the genes associate with ubiquitously expressed bHLH factors, such as E2 gene products, and thereby prevent tissue-specific bHLH factors including Ascl1 and Neurogs from forming functional complexes with the E proteins, leading to inhibition of neuronal differentiation of NSCs.…”

γ-Secretase — Regulated Signaling and Alzheimer's Disease

“…The signaling hypothesis suggests that the primary function of γ-secretase is to regulate signaling of type 1 membrane proteins (the amino terminus is extracellular, and the carboxy terminus is cytoplasmic); this was proposed by analogy of Notch signaling [13][14][15]. Notch is a family of evolutionarily conserved type 1 membrane proteins that mediate the fates of numerous cells in both invertebrates and vertebrates [16][17][18].…”

“…The ICDs of these proteins are also released from the cell membrane [13][14][15]22]. Furthermore, it has been shown that some of these ICDs exist in the nucleus.…”