Signaling by NOTCH1

Stable Identifier
R-HSA-1980143
Type
Pathway
Species
Homo sapiens
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NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.

NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.

NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2 or MAML3; possibly also MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.

Literature References
PubMed ID Title Journal Year
18094723 FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation

Welcker, M, Clurman, BE

Nat Rev Cancer 2008
11585921 SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation

Wu, G, Lyapina, S, Das, I, Li, J, Gurney, M, Pauley, A, Chui, I, Deshaies, RJ, Kitajewski, J

Mol Cell Biol 2001
8001118 Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins

Paroush, Z, Finley RL, Jr, Kidd, T, Wainwright, SM, Ingham, PW, Brent, R, Ish-Horowicz, D

Cell 1994
11044625 Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos

Leimeister, C, Schumacher, N, Steidl, C, Gessler, M

Mech Dev 2000
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
12391150 p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro

Wallberg, AE, Pedersen, K, Lendahl, U, Roeder, RG

Mol Cell Biol 2002
16530044 Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes

Nam, Y, Sliz, P, Song, L, Aster, JC, Blacklow, SC

Cell 2006
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
9244301 Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis

Pan, D, Rubin, GM

Cell 1997
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
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
16256737 Hypoxia requires notch signaling to maintain the undifferentiated cell state

Gustafsson, MV, Zheng, X, Pereira, T, Gradin, K, Jin, S, Lundkvist, J, Ruas, JL, Poellinger, L, Lendahl, U, Bondesson, M

Dev Cell 2005
14980219 A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors

Perissi, V, Aggarwal, A, Glass, CK, Rose, DW, Rosenfeld, MG

Cell 2004
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
9694793 A histone deacetylase corepressor complex regulates the Notch signal transduction pathway

Kao, HY, Ordentlich, P, Koyano-Nakagawa, N, Tang, Z, Downes, M, Kintner, CR, Evans, RM, Kadesch, T

Genes Dev 1998
18374649 TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints

Perissi, V, Scafoglio, C, Zhang, J, Ohgi, KA, Rose, DW, Glass, CK, Rosenfeld, MG

Mol Cell 2008
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
11461910 The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog

Oberg, C, Li, J, Pauley, A, Wolf, E, Gurney, M, Lendahl, U

J Biol Chem 2001
20972443 Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes

Arnett, KL, Hass, M, McArthur, DG, Ilagan, MXG, Aster, JC, Kopan, R, Blacklow, SC

Nat Struct Mol Biol 2010
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
9620803 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain

Schroeter, EH, Kisslinger, JA, Kopan, R

Nature 1998
8649374 The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain

Fisher, AL, Ohsako, S, Caudy, M

Mol Cell Biol 1996
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
8687460 Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif

Grbavec, D, Stifani, S

Biochem Biophys Res Commun 1996
15107403 The Notch target genes Hey1 and Hey2 are required for embryonic vascular development

Fischer, A, Schumacher, N, Maier, M, Sendtner, M, Gessler, M

Genes Dev 2004
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
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
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
7566092 Signalling downstream of activated mammalian Notch

Jarriault, S, Brou, C, Logeat, F, Schroeter, EH, Kopan, R, Israel, A

Nature 1995
17114293 NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth

Palomero, T, Lim, WK, Odom, DT, Sulis, ML, Real, PJ, Margolin, A, Barnes, KC, O'Neil, J, Neuberg, D, Weng, AP, Aster, JC, Sigaux, F, Soulier, J, Look, AT, Young, RA, Califano, A, Ferrando, AA

Proc Natl Acad Sci U S A 2006
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
18628966 AIP4/Itch regulates Notch receptor degradation in the absence of ligand

Chastagner, P, Israel, A, Brou, C

PLoS One 2008
10964718 Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes

Maier, MM, Gessler, M

Biochem Biophys Res Commun 2000
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
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
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
15546612 Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover

Fryer, CJ, White, JB, Jones, KA

Mol Cell 2004
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
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
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
9315665 Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor

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Mol Cell Biol 1997
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
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
12050117 Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex

Fryer, CJ, Lamar, E, Turbachova, I, Kintner, C, Jones, KA

Genes Dev 2002
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
10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function

Zhou, S, Fujimuro, M, Hsieh, JJ, Chen, L, Miyamoto, A, Weinmaster, G, Hayward, SD

Mol Cell Biol 2000
18043734 An obligatory role of mind bomb-1 in notch signaling of mammalian development

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PLoS One 2007
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
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