Notch
Transcription Factors

Author: Filippo Ciceri
Date: 22/04/2008

Description

Notch is considered to be conserved in its role of controlling embryonic organogenesis and postnatal tissue repair. The variable strength of Notch signaling represents a highly reliable molecular mechanism that regulates cell-fate determination, and enables formation of tissues and organs from initially equivalent groups of stem cells.
Likewise, we know that Notch signaling is involved with embryonic, postnatal, aged and oncogenic properties of stem and progenitor cells. The interactions between Notch signaling and other key molecular networks (e.g. transforming growth factor bone morphogenetic protein 4 and Wingless) have also been conserved in postnatal regeneration of multiple tissues, and are implicated in Notch-imposed control of stem cell responses.

Pathway components

Notch receptors

The mature Notch receptor (b) is produced through a furin cleavage during biosynthesis. Notch extracellular domains contain 29–36 EGF repeats, 3 cysteine rich LIN repeats and a region that links to the transmembrane and intracellular fragment. This linker region is important in preventing premature activation of the receptor and is altered in 26% of activating mutations that are associated with T-cell acute lymphoblastic leukaemia. EGF-repeats 11 and 12 (orange) are essential for ligand binding. The intracellular portion consists of a RAM domain, six ankyrin (Ank) repeats and a C-terminal PEST domain. It also contains nuclear localization signals. Individual types of Notch receptor have additional protein–protein interaction motifs.

DSL ligands

Notch ligands (a) are transmembrane proteins that are characterized by an N-terminal DSL (Delta, Serrate and LAG-2) domain that is essential for interactions with the Notch receptor. The ligands are subdivided into two classes,

  • Delta or Delta-like (Dll) and
  • Serrate (Jagged in mammals)

depending on the presence or absence of a cysteine rich (CR) domain.

Nuclear effectors

The key transducer of the Notch-signalling pathway is a DNA-binding protein, CSL. DNA contacts are predominantly made through the RHR-N and BTD domains. The BTD domain contains a hydrophobic pocket that is thought to mediate the interaction with the Notch intracellular domain (Nicd). To activate transcription, the co-activator Mastermind (Mam) is required.

Details of the pathway

Notch Signaling

Notch–DSL ligand binding instigates proteolytic cleavage at both the extracellular and intracellular regions of the Notch receptor. The first cleavage (S2 cleavage) is a direct consequence of ligand binding and is catalysed by the ADAM family metalloproteases- These proteases release the ligand-bound extracellular portion of Notch. These proteases release the ligand-bound extracellular portion of Notch. In S3 cleavage, release of the Notch intracellular domain (NICD) is mediated by the action of a presenilin-1- dependent gamma-secretase complex (containing presenilin, nicastrin, presenilin enhancer protein and alphaprotein [APH1]). Nuclear localization signals within the NICD direct its translocation, where it binds to and displaces a CSL transcriptional corepressor complex. In the absence of Notch activation, CSL recruits various histone deacetylases and corepressor components.

Functions

The Notch signaling pathway is important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. Notch signaling also has a role in the others processes (Wiki)

Regulation of notch ligand activity

The identification of the E3 ubiquitin ligases,

  • Neuralized (Neur)
  • Mind bomb (Mib)

that interact directly with Notch ligands and are required for ligand activation was a striking and surprising recent discovery. Some observations indicate that regulation of ligand activity by Neur and Mib is intimately associated with endocytosis.

Regulation of notch receptor activity

Role of glycosylation
Notch proteins have a large ECD that consists of multiple EGF-like repeats, which are sites for glycosylation. The enzyme O-fucosyl transferase (O-Fut) adds the first fucose and is essential for the generation of a functional receptor.
Not only is the enzymatic activity important, O-Fut also functions as a chaperone to promote the folding and transport of Notch from the endoplasmic reticulum to the cell membrane.

Papers Miele L Notch cancer

Notch signaling in cancer 2006

Notch signaling 2006

Papers Bray SJ. Notch signaling

Notch signalling: a simple pathway becomes complex 2006

Papers Stanley P. Notch signaling

Regulation of Notch signaling by glycosylation 2007

Notch at Reactome

view Tesina 2008

Comments
2013-11-11T14:58:35 - enrico fruttero

NOTCH2 mutations in Alagille syndrome

NOTCH2 domain structure and Alagille syndrome (ALGS) mutation locations. The protein
domain structure of the human NOTCH2 protein is depicted. NOTCH2 is a transmembrane
protein with intracellular and extracellular components. The extracellular part of the protein
contains 36 epidermal growth factor (EGF) repeats involved in ligand binding. The 11th and
12th of the EGF repeats (depicted in a different colour from the rest) are known to be
required for efficient ligand binding. The intracellular portion of the protein is comprised of
multiple domains, including seven ankyrin repeats (ANK) which are required for binding to
the CSL (for CBF1 (mammalian C promoter-binding factor 1), suppressor of hairless (fly)
Lag2 (worm)) transcription factor in the nucleus and activation of downstream transcription.
All of the NOTCH2 mutations identified in ALGS patients are listed in the corresponding
region of the protein

2008-04-28T16:54:03 - Filippo Ciceri

scheda realizzata da Filippo Ciceri e Gabriele Picco

notch

Four different Notch receptors (NOTCHs: NOTCH1 to NOTCH4) and five ligands (Jagged-1 (JAG1) and -2 (JAG2) and Delta-like [DLLs]: DLL1, DLL2 and DLL4) have been characterized in mammalian cells. These transmembrane receptors and ligands are expressed in different combinations in most, if not all, cell types.

The Notch pathway regulates cell fate determination of neighbouring cells through lateral inhibition, depending on their ability to express either the receptors or the ligands.

Notch family members are transmembrane receptors and developmental morphogens.

In adult tissue, activation of the NOTCH1 pathway mediates context-specific functions, such as self-renewal and T-cell differentiation. NOTCH1 signalling is initiated by the engagement of extracellular portions (ECN) of NOTCH1 with its ligands, which are members of the Jagged/Delta family.

This binding induces metalloprotease-dependent cleavage of the NOTCH1 heterodimerization domain (HD) with terminal cleavage that is dependent on gamma-secretase activity. (Notch signaling pathway)

NICD driven transcription

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