Reactome: A Curated Pathway Database

Activated NOTCH1 Transmits Signal to the Nucleus

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

Mature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. 2009) or JAG2 (Luo et al. 1997, Shimizu et al. 2000), expressed in trans on a neighboring cell. Thus, a ligand-expressing cell is a signal-sending cell, while the NOTCH1 expressing cell is a signal-receiving cell. If NOTCH1 has undergone Fringe modification in the Golgi, it is preferentially activated by Delta ligands (Yang et al. 2005), DLL1 and DLL4.

Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.

NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).

NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner et al. 2008).

Literature References
PubMed ID Title Journal Year
18237417 The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila BMC Dev Biol 2008
10879540 Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 Nature 2000
18043734 An obligatory role of mind bomb-1 in notch signaling of mammalian development PLoS One 2007
8313469 Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells Cell 1994
20418862 Cis-interactions between Notch and Delta generate mutually exclusive signalling states Nature 2010
18296446 Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity J Biol Chem 2008
15965470 DNER acts as a neuron-specific Notch ligand during Bergmann glial development Nat Neurosci 2005
9315665 Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor Mol Cell Biol 1997
9819428 Delta-1 activation of notch-1 signaling results in HES-1 transactivation Mol Cell Biol 1998
18077452 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1 J Biol Chem 2008
15652348 dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats Exp Cell Res 2005
12530964 Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta Dev Cell 2003
10206645 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Nature 1999
17003037 Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 J Biol Chem 2006
9620803 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain Nature 1998
11740940 Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta Dev Cell 2001
19567869 Numb regulates post-endocytic trafficking and degradation of Notch1 J Biol Chem 2009
15574878 Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1 Mol Biol Cell 2005
18628966 AIP4/Itch regulates Notch receptor degradation in the absence of ligand PLoS One 2008
9590294 Human deltex is a conserved regulator of Notch signalling Nat Genet 1998
11006133 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors Biochem Biophys Res Commun 2000
11226752 Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis Int J Dev Neurosci 2001
19726682 Metalloprotease ADAM10 is required for Notch1 site 2 cleavage J Biol Chem 2009
17028573 Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains EMBO Rep 2006
15824097 Mind bomb-2 is an E3 ligase for Notch ligand J Biol Chem 2005
10882063 A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE Mol Cell 2000
9462510 The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1 Immunity 1998
16284625 Regulation of Notch signalling by non-visual beta-arrestin Nat Cell Biol 2005
9244301 Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis Cell 1997
12354787 The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts Hum Mol Genet 2002
19524514 The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Cell 2009
14567914 F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Cell 2003
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