Reactome | Activated NOTCH1 Transmits Signal to the Nucleus

Activated NOTCH1 Transmits Signal to the Nucleus

Stable Identifier

R-HSA-2122948

Type

Pathway

Species

Homo sapiens

Compartment

plasma membrane, cytosol, nucleoplasm

ReviewStatus

5/5

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Activated NOTCH1 Transmits Signal to the Nucleus

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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
10879540	Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 Huppert, SS, Le, A, Schroeter, EH, Mumm, JS, Saxena, MT, Milner, LA, Kopan, R	Nature	2000
18237417	The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila Bray, SJ, Takada, S, Harrison, E, Shen, SC, Ferguson-Smith, AC	BMC Dev Biol	2008
18043734	An obligatory role of mind bomb-1 in notch signaling of mammalian development Koo, BK, Yoon, MJ, Yoon, KJ, Im, SK, Kim, YY, Kim, CH, Suh, PG, Jan, YN, Kong, YY	PLoS One	2007
8313469	Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells Rhyu, MS, Jan, LY, Jan, YN	Cell	1994
20418862	Cis-interactions between Notch and Delta generate mutually exclusive signalling states Sprinzak, D, Lakhanpal, A, LeBon, L, Santat, LA, Fontes, ME, Anderson, GA, Garcia-Ojalvo, J, Elowitz, MB	Nature	2010
18296446	Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity Cordle, J, Redfield, C, Stacey, M, van der Merwe, PA, Willis, AC, Champion, BR, Hambleton, S, Handford, PA	J Biol Chem	2008
15965470	DNER acts as a neuron-specific Notch ligand during Bergmann glial development Eiraku, M, Tohgo, A, Ono, K, Kaneko, M, Fujishima, K, Hirano, T, Kengaku, M	Nat Neurosci	2005
9315665	Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor Luo, B, Aster, JC, Hasserjian, RP, Kuo, F, Sklar, J	Mol Cell Biol	1997
9819428	Delta-1 activation of notch-1 signaling results in HES-1 transactivation Jarriault, S, Le, Bail O, Hirsinger, E, Pourquie, O, Logeat, F, Strong, CF, Brou, C, Seidah, NG, Isra, l A	Mol Cell Biol	1998
14567914	F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Hu, QD, Ang, BT, Karsak, M, Hu, WP, Cui, XY, Duka, T, Takeda, Y, Chia, W, Sankar, N, Ng, YK, Ling, EA, Maciag, T, Small, D, Trifonova, R, Kopan, R, Okano, H, Nakafuku, M, Chiba, S, Hirai, H, Aster, JC, Schachner, M, Pallen, CJ, Watanabe, K, Xiao, ZC	Cell	2003
18077452	Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1 Koutelou, E, Sato, S, Tomomori-Sato, C, Florens, LA, Swanson, SK, Washburn, MP, Kokkinaki, M, Conaway, RC, Conaway, JW, Moschonas, NK	J Biol Chem	2008
15652348	dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats Baladrón, V, Ruiz-Hidalgo, MJ, Nueda, ML, Díaz-Guerra, MJM, García-Ramírez, JJ, Bonvini, E, Gubina, E, Laborda, J	Exp Cell Res	2005
12530964	Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta Itoh, M, Kim, CH, Palardy, G, Oda, T, Jiang, YJ, Maust, D, Yeo, SY, Lorick, K, Wright, GJ, Ariza-McNaughton, L, Weissman, AM, Lewis, J, Chandrasekharappa, SC, Chitnis, AB	Dev Cell	2003
10206645	A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain De Strooper, B, Annaert, W, Cupers, P, Saftig, P, Craessaerts, K, Mumm, JS, Schroeter, EH, Schrijvers, V, Wolfe, MS, Ray, WJ, Goate, A, Kopan, R	Nature	1999
17003037	Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 Song, R, Koo, BK, Yoon, KJ, Yoon, MJ, Yoo, KW, Kim, HT, Oh, HJ, Kim, YY, Han, JK, Kim, CH, Kong, YY	J Biol Chem	2006
9620803	Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain Schroeter, EH, Kisslinger, JA, Kopan, R	Nature	1998
11740940	Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta Lai, EC, Deblandre, GA, Kintner, C, Rubin, GM	Dev Cell	2001
19567869	Numb regulates post-endocytic trafficking and degradation of Notch1 McGill, MA, Dho, SE, Weinmaster, G, McGlade, CJ	J Biol Chem	2009
15574878	Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1 Yang, LT, Nichols, JT, Yao, C, Manilay, JO, Robey, EA, Weinmaster, G	Mol Biol Cell	2005
18628966	AIP4/Itch regulates Notch receptor degradation in the absence of ligand Chastagner, P, Israel, A, Brou, C	PLoS One	2008
9590294	Human deltex is a conserved regulator of Notch signalling Matsuno, K, Eastman, D, Mitsiades, T, Quinn, AM, Carcanciu, ML, Ordentlich, P, Kadesch, T, Artavanis-Tsakonas, S	Nat Genet	1998
11006133	Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors Shimizu, K, Chiba, S, Saito, T, Kumano, K, Hirai, H	Biochem Biophys Res Commun	2000
11226752	Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis Kishi, N, Tang, Z, Maeda, Y, Hirai, A, Mo, R, Ito, M, Suzuki, S, Nakao, K, Kinoshita, T, Kadesch, T, Hui, C, Artavanis-Tsakonas, S, Okano, H, Matsuno, K	Int J Dev Neurosci	2001
19726682	Metalloprotease ADAM10 is required for Notch1 site 2 cleavage van Tetering, G, van Diest, P, Verlaan, I, van der Wall, E, Kopan, R, Vooijs, M	J Biol Chem	2009
17028573	Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains Chastagner, P, Israel, A, Brou, C	EMBO Rep	2006
15824097	Mind bomb-2 is an E3 ligase for Notch ligand Koo, BK, Yoon, KJ, Yoo, KW, Lim, HS, Song, R, So, JH, Kim, CH, Kong, YY	J Biol Chem	2005
10882063	A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE Brou, C, Logeat, F, Gupta, N, Bessia, C, LeBail, O, Doedens, JR, Cumano, A, Roux, P, Black, RA, Israel, A	Mol Cell	2000
9462510	The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1 Li, L, Milner, LA, Deng, Y, Iwata, M, Banta, AB, Graf, L, Marcovina, S, Friedman, C, Trask, BJ, Hood, L, Torok-Storb, B	Immunity	1998
16284625	Regulation of Notch signalling by non-visual beta-arrestin Mukherjee, A, Veraksa, A, Bauer, A, Rosse, C, Camonis, J, Artavanis-Tsakonas, S	Nat Cell Biol	2005
9244301	Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis Pan, D, Rubin, GM	Cell	1997
12354787	The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts Hartmann, D, De Strooper, B, Serneels, L, Craessaerts, K, Herreman, A, Annaert, W, Umans, L, Lübke, T, Lena Illert, A, von Figura, K, Saftig, P	Hum Mol Genet	2002
19524514	The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Benedito, R, Roca, C, Sörensen, I, Adams, S, Gossler, A, Fruttiger, M, Adams, RH	Cell	2009