Reactome | Pre-NOTCH Expression and Processing

Pre-NOTCH Expression and Processing

Stable Identifier

R-HSA-1912422

DOI

10.3180/REACT_118744.1

Type

Pathway

Species

Homo sapiens

Compartment

nucleoplasm, cytosol, endoplasmic reticulum membrane, endoplasmic reticulum lumen, Golgi membrane, Golgi lumen, plasma membrane

ReviewStatus

5/5

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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.

Literature References

PubMed ID	Title	Journal	Year
20351093	MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells Yeung, WS, Lee, KF, Pang, RT, Chiu, PCN, Leung, CON, Liu, W, Lam, KKW, Ye, TM	Carcinogenesis	2010
21490058	Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi Lopez, M, Fernandez-Valdivia, R, Takeuchi, H, Leonardi, J, Haltiwanger, RS, Jafar-Nejad, H, Samarghandi, A	Development	2011
9653148	The Notch1 receptor is cleaved constitutively by a furin-like convertase Seidah, NG, LeBail, O, Jarriault, S, Logeat, F	Proc Natl Acad Sci U S A	1998
11524432	Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase Shao, L, Harris, RJ, Stanley, P, Spellman, MW, Haltiwanger, RS, Shi, S, Wang, Y	J Biol Chem	2001
19773441	MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes Guessous, F, DiPierro, C, Kefas, B, Li, Y, Schiff, D, Johnson, E, Jiang, J, Purow, B, Lopes, B, Zhang, Y, Marcinkiewicz, L, Abounader, R, Yang, Y, Schmittgen, TD	Cancer Res	2009
19714243	MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells DeSano, JT, Lawrence, TS, Meng, Y, Fan, D, Bommer, GT, Fearon, ER, Xiang, D, Ji, Q, Tang, W, Hao, X, Zhang, M, Xu, L, Li, L	PLoS One	2009
21464368	Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions Wei, L, Lowe, JB, Gerson, S, Xin, W, Zhou, L, Yao, D, Stanley, P, Yan, Q, Huang, X, Wang, W, Huang, Y	Blood	2011
10669757	Calcium depletion dissociates and activates heterodimeric notch receptors Blacklow, SC, Grimm, LM, Sklar, J, Artavanis-Tsakonas, S, Patriub, V, Rand, MD	Mol Cell Biol	2000
9727485	Roles for proteolysis and trafficking in notch maturation and signal transduction Jan, YN, Chan, YM	Cell	1998
12486116	Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region Shao, L, Haltiwanger, RS, Moloney, DJ	J Biol Chem	2003
18243100	Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling Rajan, A, Pan, H, Takeuchi, H, Acar, M, Rana, NA, Haltiwanger, RS, Bellen, HJ, Jafar-Nejad, H, Ibrani, D	Cell	2008
20805998	Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells Li, Y, Kong, D, Sarkar, FH, Sethi, S, Wang, Z, Banerjee, S, Ahmad, A	PLoS One	2010
10935626	Fringe is a glycosyltransferase that modifies Notch Shao, L, Wang, Y, Johnston, SH, Irvine, KD, Stanley, P, Haltiwanger, RS, Moloney, DJ, Wilson, R, Chen, J, Vogt, TF, Panin, VM	Nature	2000
18347015	Roles of Pofut1 and O-fucose in mammalian Notch signaling Tashima, Y, Stanley, P, Stahl, M, Shi, S, Ge, C, Uemura, K	J Biol Chem	2008
21602795	Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway Moreilhon, C, Coraux, C, Robbe-Sermesant, K, Kodjabachian, L, Barbry, P, Waldmann, R, Cardinaud, B, Chevalier, B, Marcet, B, Zaragosi, LE, Jolly, T, Birembaut, P, Nawrocki-Raby, B, Cibois, M, Luxardi, G, Giovannini-Chami, L	Nat Cell Biol	2011
11707585	Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1 Chen, J, Stanley, P, Moloney, DJ	Proc Natl Acad Sci U S A	2001
19723635	MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation Song, G, Wang, L, Zhang, Y	J Biol Chem	2009
20080834	Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis Yuasa, Y, Akiyama, Y, Shimada, S, Hashimoto, Y, Otsubo, T	Carcinogenesis	2010
9244302	Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane Artavanis-Tsakonas, S, Zagouras, P, Qi, H, Blaumueller, CM	Cell	1997
9207795	Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila Bashirullah, A, Whiting, E, Phillips, RA, Boulianne, G, Egan, SE, Campbell, C, Hui, CC, Zinyk, D, Dagnino, L, Fisher, WW, Lipshitz, HD, Leow, CC, Cohen, B, Ryan, D, Gallie, B	Nat Genet	1997
10935637	Glycosyltransferase activity of Fringe modulates Notch-Delta interactions Brückner, K, Cohen, S, Perez, L, Clausen, H	Nature	2000
20495621	Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment Arndt, K, Costa, FF, Bischof, JM, Seftor, EA, Soares, MB, Hendrix, MJC, Kirschmann, DA, de Fatima Bonaldo, M, Strizzi, L	Epigenomics	2009
9187150	A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway Prabhakaran, B, Johnston, SH, Irvine, KD, Rauskolb, C, Wilson, R, Vogt, TF	Development	1997
21551231	Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150 Bronte, V, Indraccolo, S, Basso, G, Gerosa, G, D'Agostino, DM, Amadori, A, Mussolin, L, Guffanti, A, Basso, K, De Bellis, G, Stellin, G, Ruggero, K, Ghisi, M, Frasson, C, Zanovello, P, Mukherjee, S, Corradin, A, Bonanno, L, Serafin, V	Blood	2011
19701457	Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2 L'Heureux, S, McArthur, DG, Blacklow, SC, Malecki, MJ, Mitchell, JL, Vardar-Ulu, D, Sanchez-Irizarry, C, Aster, JC, Ashworth, T, Gordon, WR, Histen, G	PLoS One	2009