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.
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMedEurope PMCScholia
Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J.; ''Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.''; PubMedEurope PMCScholia
Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD.; ''SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.''; PubMedEurope PMCScholia
Sprinzak D, Lakhanpal A, Lebon L, Santat LA, Fontes ME, Anderson GA, Garcia-Ojalvo J, Elowitz MB.; ''Cis-interactions between Notch and Delta generate mutually exclusive signalling states.''; PubMedEurope PMCScholia
Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMedEurope PMCScholia
Shao L, Moloney DJ, Haltiwanger R.; ''Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region.''; PubMedEurope PMCScholia
Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, Kadesch T, Artavanis-Tsakonas S.; ''Human deltex is a conserved regulator of Notch signalling.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMedEurope PMCScholia
Struhl G, Adachi A.; ''Nuclear access and action of notch in vivo.''; PubMedEurope PMCScholia
Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC.; ''Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2.''; PubMedEurope PMCScholia
Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC.; ''Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.''; PubMedEurope PMCScholia
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.; ''NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.''; PubMedEurope PMCScholia
Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY, Kim CH, Suh PG, Jan YN, Kong YY.; ''An obligatory role of mind bomb-1 in notch signaling of mammalian development.''; PubMedEurope PMCScholia
Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, Ando K, Zuklys S, Holländer GA, Shima DT, Habu S.; ''Delta-like 4 is indispensable in thymic environment specific for T cell development.''; PubMedEurope PMCScholia
Baladrón V, Ruiz-Hidalgo MJ, Nueda ML, DÃaz-Guerra MJ, GarcÃa-RamÃrez JJ, Bonvini E, Gubina E, Laborda J.; ''dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats.''; PubMedEurope PMCScholia
Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S.; ''Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.''; PubMedEurope PMCScholia
Song R, Koo BK, Yoon KJ, Yoon MJ, Yoo KW, Kim HT, Oh HJ, Kim YY, Han JK, Kim CH, Kong YY.; ''Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1.''; PubMedEurope PMCScholia
Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH.; ''The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.''; PubMedEurope PMCScholia
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.; ''The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.''; PubMedEurope PMCScholia
Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMedEurope PMCScholia
Fisher AL, Ohsako S, Caudy M.; ''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.''; PubMedEurope PMCScholia
Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, Pierres M, Manley NR, Duarte A, Macdonald HR, Radtke F.; ''Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.''; PubMedEurope PMCScholia
Chastagner P, Israël A, Brou C.; ''Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains.''; PubMedEurope PMCScholia
Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G.; ''Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.''; PubMedEurope PMCScholia
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.; ''Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta.''; PubMedEurope PMCScholia
Rhyu MS, Jan LY, Jan YN.; ''Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells.''; PubMedEurope PMCScholia
Lecourtois M, Schweisguth F.; ''Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos.''; PubMedEurope PMCScholia
Chen J, Moloney DJ, Stanley P.; ''Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.''; PubMedEurope PMCScholia
Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA.; ''Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.''; PubMedEurope PMCScholia
Nam Y, Sliz P, Song L, Aster JC, Blacklow SC.; ''Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.''; PubMedEurope PMCScholia
Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J.; ''SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.''; PubMedEurope PMCScholia
Welcker M, Clurman BE.; ''FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.''; PubMedEurope PMCScholia
Oka C, Nakano T, Wakeham A, de la Pompa JL, Mori C, Sakai T, Okazaki S, Kawaichi M, Shiota K, Mak TW, Honjo T.; ''Disruption of the mouse RBP-J kappa gene results in early embryonic death.''; PubMedEurope PMCScholia
Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA, Kopan R.; ''Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.''; PubMedEurope PMCScholia
Chastagner P, Israël A, Brou C.; ''AIP4/Itch regulates Notch receptor degradation in the absence of ligand.''; PubMedEurope PMCScholia
Rustighi A, Tiberi L, Soldano A, Napoli M, Nuciforo P, Rosato A, Kaplan F, Capobianco A, Pece S, Di Fiore PP, Del Sal G.; ''The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer.''; PubMedEurope PMCScholia
Grbavec D, Stifani S.; ''Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif.''; PubMedEurope PMCScholia
Cohen B, Bashirullah A, Dagnino L, Campbell C, Fisher WW, Leow CC, Whiting E, Ryan D, Zinyk D, Boulianne G, Hui CC, Gallie B, Phillips RA, Lipshitz HD, Egan SE.; ''Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.''; PubMedEurope PMCScholia
Fortini ME.; ''Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling.''; PubMedEurope PMCScholia
Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMedEurope PMCScholia
Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y.; ''Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.''; PubMedEurope PMCScholia
Perissi V, Scafoglio C, Zhang J, Ohgi KA, Rose DW, Glass CK, Rosenfeld MG.; ''TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.''; PubMedEurope PMCScholia
Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMedEurope PMCScholia
Arnett KL, Hass M, McArthur DG, Ilagan MX, Aster JC, Kopan R, Blacklow SC.; ''Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.''; PubMedEurope PMCScholia
Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMedEurope PMCScholia
Lai EC, Deblandre GA, Kintner C, Rubin GM.; ''Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta.''; PubMedEurope PMCScholia
Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J.; ''TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.''; PubMedEurope PMCScholia
Ghisi M, Corradin A, Basso K, Frasson C, Serafin V, Mukherjee S, Mussolin L, Ruggero K, Bonanno L, Guffanti A, De Bellis G, Gerosa G, Stellin G, D'Agostino DM, Basso G, Bronte V, Indraccolo S, Amadori A, Zanovello P.; ''Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.''; PubMedEurope PMCScholia
Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML, Aster JC, Blacklow SC.; ''Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes.''; PubMedEurope PMCScholia
Wang Y, Shao L, Shi S, Harris RJ, Spellman MW, Stanley P, Haltiwanger RS.; ''Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase.''; PubMedEurope PMCScholia
Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A.; ''The Notch1 receptor is cleaved constitutively by a furin-like convertase.''; PubMedEurope PMCScholia
Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH, Kim CH, Kong YY.; ''Mind bomb-2 is an E3 ligase for Notch ligand.''; PubMedEurope PMCScholia
Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R.; ''MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes.''; PubMedEurope PMCScholia
Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, Kengaku M.; ''DNER acts as a neuron-specific Notch ligand during Bergmann glial development.''; PubMedEurope PMCScholia
Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF.; ''A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway.''; PubMedEurope PMCScholia
Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMedEurope PMCScholia
Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMedEurope PMCScholia
Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMedEurope PMCScholia
Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U.; ''The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.''; PubMedEurope PMCScholia
Hori K, Sen A, Kirchhausen T, Artavanis-Tsakonas S.; ''Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal.''; PubMedEurope PMCScholia
McGill MA, Dho SE, Weinmaster G, McGlade CJ.; ''Numb regulates post-endocytic trafficking and degradation of Notch1.''; PubMedEurope PMCScholia
Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B.; ''The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.''; PubMedEurope PMCScholia
Fernandez-Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, Jafar-Nejad H.; ''Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi.''; PubMedEurope PMCScholia
Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K, Hori K, Taniguchi-Kanai M, Franklin E, Matsuno K, Baron M.; ''Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway.''; PubMedEurope PMCScholia
Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M.; ''The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.''; PubMedEurope PMCScholia
Chan YM, Jan YN.; ''Roles for proteolysis and trafficking in notch maturation and signal transduction.''; PubMedEurope PMCScholia
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.; ''Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis.''; PubMedEurope PMCScholia
Stahl M, Uemura K, Ge C, Shi S, Tashima Y, Stanley P.; ''Roles of Pofut1 and O-fucose in mammalian Notch signaling.''; PubMedEurope PMCScholia
Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M.; ''Hypoxia requires notch signaling to maintain the undifferentiated cell state.''; PubMedEurope PMCScholia
Costa FF, Seftor EA, Bischof JM, Kirschmann DA, Strizzi L, Arndt K, Bonaldo Mde F, Soares MB, Hendrix MJ.; ''Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment.''; PubMedEurope PMCScholia
Song G, Zhang Y, Wang L.; ''MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation.''; PubMedEurope PMCScholia
Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, Sarkar FH.; ''Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells.''; PubMedEurope PMCScholia
Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMedEurope PMCScholia
Pitsouli C, Delidakis C.; ''The interplay between DSL proteins and ubiquitin ligases in Notch signaling.''; PubMedEurope PMCScholia
Marcet B, Chevalier B, Luxardi G, Coraux C, Zaragosi LE, Cibois M, Robbe-Sermesant K, Jolly T, Cardinaud B, Moreilhon C, Giovannini-Chami L, Nawrocki-Raby B, Birembaut P, Waldmann R, Kodjabachian L, Barbry P.; ''Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.''; PubMedEurope PMCScholia
Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T.; ''A histone deacetylase corepressor complex regulates the Notch signal transduction pathway.''; PubMedEurope PMCScholia
Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS, Xu L.; ''MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.''; PubMedEurope PMCScholia
Pan D, Rubin GM.; ''Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis.''; PubMedEurope PMCScholia
Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMedEurope PMCScholia
Lai EC, Roegiers F, Qin X, Jan YN, Rubin GM.; ''The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta.''; PubMedEurope PMCScholia
Wallberg AE, Pedersen K, Lendahl U, Roeder RG.; ''p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.''; PubMedEurope PMCScholia
Cordle J, Redfieldz C, Stacey M, van der Merwe PA, Willis AC, Champion BR, Hambleton S, Handford PA.; ''Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity.''; PubMedEurope PMCScholia
Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S.; ''Regulation of Notch signalling by non-visual beta-arrestin.''; PubMedEurope PMCScholia
Cordle J, Johnson S, Tay JZ, Roversi P, Wilkin MB, de Madrid BH, Shimizu H, Jensen S, Whiteman P, Jin B, Redfield C, Baron M, Lea SM, Handford PA.; ''A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.''; PubMedEurope PMCScholia
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMedEurope PMCScholia
Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG.; ''A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.''; PubMedEurope PMCScholia
Kang JS, Liu C, Derynck R.; ''New regulatory mechanisms of TGF-beta receptor function.''; PubMedEurope PMCScholia
Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMedEurope PMCScholia
Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC.; ''Structural basis for autoinhibition of Notch.''; PubMedEurope PMCScholia
Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF.; ''Fringe is a glycosyltransferase that modifies Notch.''; PubMedEurope PMCScholia
Koutelou E, Sato S, Tomomori-Sato C, Florens L, Swanson SK, Washburn MP, Kokkinaki M, Conaway RC, Conaway JW, Moschonas NK.; ''Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1.''; PubMedEurope PMCScholia
Pang RT, Leung CO, Ye TM, Liu W, Chiu PC, Lam KK, Lee KF, Yeung WS.; ''MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells.''; PubMedEurope PMCScholia
Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ.; ''Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling.''; PubMedEurope PMCScholia
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.; ''F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.''; PubMedEurope PMCScholia
Bray SJ, Takada S, Harrison E, Shen SC, Ferguson-Smith AC.; ''The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila.''; PubMedEurope PMCScholia
Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI.; ''Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line.''; PubMedEurope PMCScholia
van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M.; ''Metalloprotease ADAM10 is required for Notch1 site 2 cleavage.''; PubMedEurope PMCScholia
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.; ''A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.''; PubMedEurope PMCScholia
Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A.; ''Signalling downstream of activated mammalian Notch.''; PubMedEurope PMCScholia
Paroush Z, Finley RL, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D.; ''Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins.''; PubMedEurope PMCScholia
Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMedEurope PMCScholia
Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMedEurope PMCScholia
Fryer CJ, White JB, Jones KA.; ''Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.''; PubMedEurope PMCScholia
Le Borgne R, Remaud S, Hamel S, Schweisguth F.; ''Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila.''; PubMedEurope PMCScholia
Yao D, Huang Y, Huang X, Wang W, Yan Q, Wei L, Xin W, Gerson S, Stanley P, Lowe JB, Zhou L.; ''Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions.''; PubMedEurope PMCScholia
Shimizu K, Chiba S, Saito T, Kumano K, Hirai H.; ''Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMedEurope PMCScholia
Leimeister C, Schumacher N, Steidl C, Gessler M.; ''Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos.''; PubMedEurope PMCScholia
Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israël A.; ''A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.''; PubMedEurope PMCScholia
Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.
During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
In a small percent of T-ALL patients, the translocation t(7;9)(q34;q34.3) fuses intron 24 of NOTCH1 gene with the promoter of T cell receptor beta gene. This results in deregulated expression of a truncated NOTCH1 protein, which lacks ligand binding activity and is constitutivelu processed into NICD1 (Ellisen et al. 1991).
In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).
The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).
In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases. TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1. The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex. In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner. The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
NEXT1 fragment of NOTCH1 is further cleaved at S3 by the presenilin-1 (PSEN1) containing gamma-secretase complex, which releases the intracellular domain NICD1 into the cytosol (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini et al. 2002). PIN1, a prolyl isomerase, was recently found to bind phosphorylated Ser/Thr-Pro motifs in the cytoplasmic domain of NOTCH1 and potentiate NEXT1 cleavage by gamma-secretase. This generates a positive loop in NOTCH1 signaling since PIN1 is a transcriptional target of NICD1 (Rustighi et al. 2009).
Ligand binding induces a conformational change in NOTCH1, probably through mechanical stretching of NOTCH1 triggered by endocytosis of the ligand attached to the receptor. This conformational change exposes the S2 site in the extracellular region of NOTCH1 and results in cleavage of NOTCH1 by ADAM10 metalloprotease, the mammalian homolog of Kuzbanian (Pan and Rubin, 1997), generating the membrane-anchored NOTCH1 fragment NEXT1.This model is supported by the crystal structure of human NOTCH2 negative regulatory region, showing that NOTCH adopts an autoinhibited conformation where extensive interdomain interactions within the negative regulatory region bury S2. A substantial conformational movement, triggered by ligand binding in trans, is needed to expose S2 (Gordon et al. 2007). After S2 cleavage, the extracellular NOTCH1 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. ADAM17 is able to perform cleavage at the S2 site in vitro (Brou et al. 2000), but ADAM10 was shown to be necessary in studies done on mouse cell lines deficient in different ADAM enzymes (van Tetering et al. 2009). Adam10 knockout mice die at embryonic day 9.5 with multiple defects in the developing central nervous system, somites and cardiovascular system and exhibit decreased expression of the Notch target Hes5 in the neural tube (Hartmann et al. 2002).
Once bound to FBXW7, phosphorylated NICD1 is ubiquitinated, which leads to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on the C-terminally located PEST domain of NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain in NOTCH1 and the substrate binding WD40 domain in FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008).
Enhancer of split, a Drosophila orthologue of HES, is a basic-helix-loop-helix (bHLH) protein that represses transcription during Drosophila nervous system development. Groucho, the Drosophila homologue of TLE proteins, binds to the WRPW motif of Enhancer of split, resulting in the formation of a transcriptional co-repressor involved in the regulation of neurogenesis, segmentation and sex determination (Paroush et al. 1994). The interaction of HES1 and TLE proteins is conserved in mammals and the WRPW motif of HES1 plays the key role in the formation of HES1:TLE complex (Fisher et al. 1996, Grbavec and Stifani 1996).
The E3 ubiquitin ligase FBXW7, a homologue of C. elegans sel-10, binds phosphorylated NOTCH1 intracellular domain, p-NICD1 (Oberg et al. 2001, Fryer et al. 2004, Wu et al. 2001). FBXW7 is a substrate recognition component of an E3 ubiquitin-protein ligase complex that also contains SKP1, CUL1 and RBX1. FBXW7 has three transcriptional isoforms, known as FBXW7 alpha, FBXW7 beta and FBXWT gamma. While FBXW7 beta is cytosolic, FBXW7 alpha and gamma are nuclear, with FBXW7 gamma localizing to the nucleolus. FBXW7 alpha is the most abundant isoform and the one directly shown to interact with NICD1 (Welcker and Clurman 2008).
In the absence of NICD1, RBPJ (CSL) is bound to a co-repressor complex that includes NCOR proteins, NCOR1 and/or NCOR2 (also known as SMRT) and HDAC histone deacetylases. Both NCOR and HDAC proteins interact with RBPJ (CSL) through a repression domain in RBPJ. When bound to the co-repressor complex, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998). The co-repressor complex also contains SNW1 (SKIP), which interacts with RBPJ (CSL) in a repression-domain independent way (Zhou et al. 2000), TBL1X (TBL1) and TBL1XR1 (TBLR1) (Perissi et al. 2004). NICD1 binds to RBPJ (CSL) and SNW1 (SKIP) and displaces NCOR and HDAC proteins (Kao et al. 1998). TBL1X and TBL1XR1 facilitate displacement of NCOR and HDAC and positively regulated NOTCH-mediated transcription probably by recruiting the ubiquitin/19S proteasome complex that degrades transcriptional repressors (Perissi et al. 2004, Perissi et al. 2008). SNW1 facilitates NICD1 interaction with RBPJ and NOTCH-mediated transcription (Zhou et al. 2000). It is possible that the co-repressor complex contains additional proteins not described here. Loss-of-function mutations in RBPJ typically result in phenotypes associated with reduced NOTCH function, suggesting that RBPJ activation complex (i.e. NOTCH coactivator complex) is more important than RBPJ repressor complex in control of normal development and homeostasis (Oka et al. 1995).
CDK8 phosphorylates conserved serine residues in the TAD and PEST domains of NICD1. Phosphorylation targets NICD1 for ubiquitination and degradation, ultimately terminating transcriptional activity of NOTCH1 (Fryer et al. 2004).
After NOTCH1 coactivator complex is assembled on a NOTCH-target promoter, MAML (mastermind-like) recruits CDK8 in complex with cyclin C (CDK:CCNC) (Fryer et al. 2004).
The minimal functional NOTCH coactivator complex that activates transcription from NOTCH regulatory elements is a heterotrimer composed of MAML (mastermind-like), NICD (NOTCH intracellular domain) and RBPJ (CSL) (Fryer et al. 2002). Structural studies indicate that NOTCH:RBPJ complexes can be pre-assembled on promoters of NOTCH-target genes and that MAML binds to a composite groove created by RBPJ and the NOTCH ankyrin domain (Nam et al. 2006). MAML is able to interact directly with a histone acetyltransferases EP300 (p300) and CREBBP. The presence of EP300 strongly activates NOTCH1 coactivator complex-mediated transcription and this positive effect is blocked by Lys-CoA, a selective inhibitor of EP300 histone acetyltransferase activity (Fryer et al. 2002). NICD1:RBPJ:MAML-mediated transcription increases threefold in the presence of both EP300 and PCAF, in comparison with the presence of EP300 alone (Wallberg et al. 2002).
When the oxygen supply is low, hypoxia-inducible factor 1-alpha (HIF1A) accumulates in the nucleus where it binds and prolongs the half-life of NICD1, resulting in increased NICD1-mediated transcription and consequent inhibition of cellular differentiation.
DNER is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. DNER has ten extracellular EGF repeats highly homologous to EGF repeats of Notch and Delta proteins, but does not contain a typical DSL domain. DNER binds NOTCH1 and this interaction involves the first and second EGF repeat of DNER. Activation of NOTCH1 signaling by DNER requires the presence of deltex (DTX1, DTX2 and/or DTX4). The interaction of DNER and NOTCH may be playing an important role in the development of the central nervous system by influencing the differentiation of astrocytes, based on mouse studies.
The NOTCH1 receptor is activated by binding Delta-like 1 ligand (DLL1), presented on the plasma membrane of a neighboring cell (Jarriault et al. 1998). EGF repeat 12 (EGF12) in the extracellular domain of NOTCH1 appears to be particularly important for interaction of NOTCH1 with DLL1 (Cordle et al. 2008). The affinity of NOTCH1 for DLL1 is increased when NOTCH1 is glycosylated by fringe enzymes (Yang et al 2005).
NOTCH1 is activated by DLL4 ligand expressed on a neighboring cell. The interaction of NOTCH1 and DLL4 is enhanced when NOTCH1 is glycosylated by fringe-enzymes. Based on mouse studies, activation of NOTCH1 by DLL4 may be important in angiogenesis (Benedito et al. 2009). DLL4 may also be involved in T-cell development. Mouse Dll4 is expressed on thymic epithelial cells and its interaction with Notch1 expressed on hematopoietic progenitors is necessary for T-cell lineage commitment (Koch et al. 2008, Hozumi et al. 2008).
NOTCH1 is activated by JAG1 ligand expressed on a neighboring cell. Based on mouse studies, activation of NOTCH1 by JAG1 may be important in angiogenesis (Benedito et al. 2009). In addition, human JAG1 was shown to inhibit granulocytic differentiation of 32D mouse myeloid progenitors expressing Notch1 (Li et al. 1998).
NOTCH1 is activated by JAG2 ligand expressed on a neighboring cell. When the mouse myoblast cell line C2C12 expressing exogenous human NOTCH1 is grown with NIH3T3 cells expressing exogenous human JAG2, myogenic differentiation is inhibited and a NOTCH1 polypeptide that corresponds to the NOTCH intracellular domain appears (Luo et al. 1997).
NOTCH1 coactivator complex binds the promoter of HES1 gene and directly stimulates HES1 transcription. HES1 belongs to the bHLH family of transcription factors (Jarriault et al. 1995).
RBPJ binding sites in the promoters of HEY1, HEY2 and HEYL genes are conserved between humans and mice (Maier and Gessler 2000), and expression of human NICD1 was directly shown to activate transcription from human HEY2 and HEYL promoters (Arnett et al. 2010). Based on the evolutionary conservation of RBPJ sites and the existing findings from human and mouse studies, NOTCH1 is expected to directly stimulate transcription of HEY1, HEY2 and HEYL (Fischer et al. 2004, Leimeister et al. 2000).
NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH1 in trans. In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse Neurl was directly shown to ubiquitinate Jag1 but not other Notch ligands in vitro. N-terminal myristoylation targets Neurl to the plasma membrane and this is a prerequisite for Jag1 internalization (Koutelou et al. 2008). Mouse Neurl1b was shown to directly bind and ubiquitinate recombinant Xenopus Delta and to cooperate with Mib1 in Delta endocytosis (Song et al. 2006). Ubiquitination of NOTCH ligands by MIB and NEURL ubiquitin ligases triggers ligand endocytosis. Drosophila Neuralized needs to interact with membrane phosphoinositides through its phosphoinositide-binding motif to trigger endocytosis of ubiquitinated Delta (Skwarek et al. 2007). Endocytosis of ubiquitinated Notch ligands is thought to mechanically stretch the ligand-bound Notch receptor, exposing the S2 cleavage site and resulting in Notch receptor cleavage by ADAM10 and/or ADAM17 metalloproteases (Itoh et al. 2003).
Binding of NOTCH1 to CNTN1 (contactin-1) is followed by gamma-secretase mediated cleavage of NOTCH1 at the S3 cleavage site and accumulation of NICD1 in the nucleus. Cleavage of NOTCH1 by ADAM10/17 at the S2 cleavage site, which should precede the S3 cleavage by gamma-secretase, has not been studied in the context of NOTCH1 activation by CNTN1. NOTCH activation by CNTN1 is deltex-dependent, but the exact mechanism for action of the NOTCH:DTX complex has not yet been elucidated.
Binding of DNER to NOTCH1 induces gamma-secretase dependent cleavage of NOTCH1 at the S3 cleavage site and releases NOTCH1 intracellular domain into the cytosol. Cleavage of NOTCH1 at the S2 cleavage site by ADAM10/17, which should precede cleavage at the S3 site, has not been studied in the context of DNER-mediated NOTCH1 activation.
Ubiquitination of NOTCH1 mediated by DTX-recruited beta-arrestins (ARRB) has not been directly studied in mammals. Non-visual beta arrestins ARRB1 and ARRB2 are known to facilitate ubiquitination and downregulation of GPCRs and IGF1R.
Deltex (DTX) protein family in mammals includes four proteins: DTX1, DTX2, DTX3 and DTX4. Human DTX1 interacts with cdc10/ankyrin repeats of the intracellular domain of NOTCH1 and NOTCH2, similar to the interaction of Drosophila deltex and notch proteins (Matsuno et al. 1998). Studies on mouse deltex proteins showed that the N-terminal region of Dtx1, homologous to the Drosophila deltex domain I, is necessary and sufficient to bind the ankyrin repeats of Notch. Besides Dtx1, this Notch-interacting region is conserved in Dtx2 and Dtx4. Dtx3 lacks most of the N-terminal sequence homologous to Drosophila deltex domain I and cannot bind ankyrin repeats of mouse Notch1, while Dtx1, Dtx2 and Dtx4 bind to it strongly. Dtx3 also has a different class of RING finger domain than the other three deltex proteins (Kishi et al. 2001). While deltex colocalizes with Notch at the plasma membrane and in the cytosol, there is no colocalization between NICD and deltex in the nucleus, suggesting that DTX does not mediate NOTCH signaling by direct interaction with nuclear NICD (Matsuno et al. 1998). Recent studies in Drosophila indicate that Deltex, acting as an E3 ubiquitin ligase, may activate ligand independent Notch proteolysis and signaling by shunting Notch into an endocytic pathway that involves HOPS and AP-3 complexes (Wiklin et al. 2008).
Formation of a complex involving NOTCH, Deltex (DTX) and non-visual beta-arrestin (ARRB) has not been directly studied in mammalian cells. The mammalian non-visual beta-arrestins ARRB1 and ARRB2 play a major role in desensitization and endocytosis of G-protein-coupled receptors (GPCRs), and their interaction with GPCRs involves N-terminal beta-arrestin sequences that are homologous to the Deltex-binding N-terminus of Drosophila Kurtz (Mukherjee et al. 2005). Shrub, a core component of the ESCRT-III complex, was recently identified as an important modulator of non-visual beta-arrestin-mediated downregulation of Notch in Drosophila (Hori et al. 2011).
Genetic studies in Drosophila identified deltex as a positive regulator of Notch signaling, while the Drosophila homologue of ITCH (AIP4) was identified as a negative regulator of Notch signaling and named suppressor of deltex. ITCH and DTX1 interact and form a complex, as determined by co-immunoprecipitaion experiments in human embryonic kidney cell line HEK293 in which tagged recombinant human DTX1 and ITCH were expressed. It is not known whether this complex involves other proteins, but its formation is NOTCH-independent. Both DTX1 and ITCH are ubiquitin ligases. DTX1 is a RING-type ubiquitin ligase, while ITCH is a HECT-type ubiquitin ligase. The ubiquitin ligase activity of either protein is not needed for the formation of the DTX1:ITCH complex, and the inactive ITCH mutant co-immunoprecipitates more DTX1 than the wild-type ITCH, implicating the ubiquitin ligase activity of ITCH in DTX1 degradation.
Genetic studies in Drosophila have identified Numb as an inhibitor of Notch signaling during development of the peripheral and central nervous systems as well as muscle cell differentiation. Both Drosophila and mammalian Numb are asymmetrically localized in dividing precursor cells, ensuring that cells adopt distinct cell fates through suppression of Notch signaling in one daughter cell (Rhyu et al. 1994). NUMB recruits E3 ubiquitin ligase ITCH (AIP4) to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009).
DLK1 is a Delta-like transmembrane protein with six extracellular EGF repeats and a short intracellular tail. DLK1 is encoded by a paternally imprinted gene and, based on mouse studies, is implicated in many developmental processes, such as adipogenesis, hematopoiesis, differentiation of adrenal gland and other neuroendocrine cells, as well as development of the central nervous system. Mice lacking Dlk1 exhibit growth retardation and obesity. Based on studies done in mice and flies, NOTCH1 and DLK1 interact to form a complex, most likely in cis, which results in the inhibition of NOTCH1 signaling by preventing NOTCH1 interaction with DLL and JAG ligands (Baladron et al. 2005, Bray et al. 2008). Besides its inhibitory role, DLK1 may function as a coactivator for NOTCH receptors. DLK1 possesses a Delta and OSM-11 motif (DOS), which has been found in C. elegans proteins that facilitate Notch activation in trans by DSL family ligands. The mammalian DLK1 can substitute for OSM-11 protein in C. elegans development (Komatsu et al. 2008).
Binding of NOTCH1 to DLL/JAG ligands expressed in the same cells (in cis) blocks NOTCH1 activation by DLL/JAG ligands expressed on neighboring cells (in trans). Cis-inhibiton of NOTCH signaling can amplify small differences in NOTCH and DLL/JAG levels between neighboring cells.
NOTCH1 HD domain mutants are cleaved at S2 and S3 sites to produce NEXT1 and NICD1 fragments, respectively, in the absence of DLL/JAG ligand binding, although they are responsive to DLL/JAG ligands. NOTCH1 mutants containing in cis mutations in the HD and PEST domains are expected to be constitutively cleaved at the S2 site by ADAM10/17, like NOTCH1 HD domain mutants (Malecki et al. 2006), resulting in release of NEXT1 PEST domain mutant fragments.
NOTCH1 t(7;9)(NOTCH1:M1580_K2555) translocation mutant is susceptible to ADAM10/17-mediated cleavage in the absence of ligand binding (Ellisen et al. 1991).
When the gamma-secretase complex is inhibited, the transmembrane fragment of NOTCH1 HD domain mutants that corresponds in size to ADAM10/17 cleavage product NEXT1 accumulates in treated cells. This serves as indirect evidence of cleavage of NOTCH1 heterodimerization domain mutants by ADAM10/17 metalloprotease(s). Importantly, in the case of NOTCH1 HD domain mutants, NEXT1 fragment, as well as the gamma-secretase cleavage product NICD1, are detectable in the absence of DLL/JAG ligand binding. Therefore, NOTCH1 HD domain mutants, although capable of and responsive to ligand binding, are constitutively active because of S2 site cleavage by ADAM10/17 in the absence of ligand. The constitutive S2 site cleavage of NOTCH1 HD domain mutants could be due to their altered conformation or due to increased rate of spontaneous dissociation of NOTCH1 extracellular and transmembrane subunits (Malecki et al. 2006). Both of these scenarios could make the S2 site constitutively accessible to ADAM10/17, but the exact mechanism has not been established.
Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD domain mutants has not been investigated but is assumed to occur based on the behavior of the wild-type NOTCH1 (Lai et al. 2001, Itoh et al. 2003, Koo et al. 2005, Lai et al. 2005, Le Borgne et al. 2005, Pistouli et al. 2005, Song et al. 2006, Koo et al. 2007, Koutelou et al. 2008).
Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD+PEST domain mutants has not been investigated but is assumed to occur based on the behavior of the wild-type NOTCH1 (Lai et al. 2001, Itoh et al. 2003, Koo et al. 2005, Lai et al. 2005, Le Borgne et al. 2005, Pistouli et al. 2005, Song et al. 2006, Koo et al. 2007, Koutelou et al. 2008).
Contactin-1 (CNTN1) is composed of six Ig domains followed by four FNIII repeats and is anchored to the membrane via a glycosyl-phosphatidylinositol (GPI) tail. It is expressed transiently during CNS and PNS development both as GPI-anchored and soluble forms. CNTN1 is a physiological ligand of NOTCH, shown to bind and activate NOTCH1 and NOTCH2 in trans. The activation of NOTCH signaling by CNTN1 is Deltex (DTX)-dependent and promotes oligodendrocyte maturation and myelination.
RBPJ binding sites in the promoters of HEY1, HEY2 and HEYL genes are conserved between humans and mice (Maier and Gessler 2000), and human NICD1 was directly shown to bind human HEY2 and HEYL promoters (Arnett et al. 2010).
Neurobeachin (NBEA) is largely present in the cytoplasmic fraction of the cell, but a small portion of NBEA is nuclear. A nuclear localization signal (NLS) maps to the domain of unknown function (DUF1088) of NBEA and plays a role in translocation to the nucleus (Tuand et al. 2016).
In the nucleus, NBEA binds to the NOTCH1 intracellular domain (NICD1). This interaction involves the DPBW module of NBEA, which consists of DUF1088, PH-like, and BEACH domains, and WD40 repeats. NBEA negatively regulates transcription of NOTCH1-target genes through an unknown mechanism (Tuand et al. 2016). The interaction between NBEA and NOTCH1 may be relevant for the etiology of the autism spectrum disorders (ASD), as NBEA is an ASD candidate gene (Nuytens et al. 2013) while NOTCH signaling plays an important role in neuronal development (reviewed by Cau and Blader 2009, Ables et al. 2011, Giniger 2012, Zhang et al. 2018).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
HD+PEST Domain
MutantsDuring early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).
During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
HD domain mutant
fragments/Ub-DLL/JAG:NOTCH1 HD domain mutant fragmentsHD domain
mutants/Ub-DLL/JAG:NOTCH1 HD domain mutantsHD+PEST Domain Mutant
Fragments/Ub-DLL/JAG:NOTCH1 HD+PEST Domain Mutant FragmentsHD+PEST Domain
Mutants/Ub-DLL/JAG:NOTCH1 HD+PEST Domain MutantsThe nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).
In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
TGF-beta Receptor
ComplexTGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
HD+PEST Domain
MutantsAnnotated Interactions
HD+PEST Domain
MutantsHD domain mutant
fragments/Ub-DLL/JAG:NOTCH1 HD domain mutant fragmentsHD domain
mutants/Ub-DLL/JAG:NOTCH1 HD domain mutantsHD+PEST Domain Mutant
Fragments/Ub-DLL/JAG:NOTCH1 HD+PEST Domain Mutant FragmentsHD+PEST Domain
Mutants/Ub-DLL/JAG:NOTCH1 HD+PEST Domain MutantsHD+PEST Domain
Mutants