Pre-NOTCH Expression and Processing

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R-HSA-1912422
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Homo sapiens
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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
21464368 Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions

Yao, D, Huang, Y, Huang, X, Wang, W, Yan, Q, Wei, L, Xin, W, Gerson, S, Stanley, P, Lowe, JB, Zhou, L

Blood 2011
20351093 MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells

Pang, RT, Leung, CON, Ye, TM, Liu, W, Chiu, PCN, Lam, KKW, Lee, KF, Yeung, WS

Carcinogenesis 2010
10669757 Calcium depletion dissociates and activates heterodimeric notch receptors

Rand, MD, Grimm, LM, Artavanis-Tsakonas, S, Patriub, V, Blacklow, SC, Sklar, J

Mol Cell Biol 2000
9727485 Roles for proteolysis and trafficking in notch maturation and signal transduction

Chan, YM, Jan, YN

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, Moloney, DJ, Haltiwanger, RS

J Biol Chem 2003
18243100 Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling

Acar, M, Jafar-Nejad, H, Takeuchi, H, Rajan, A, Ibrani, D, Rana, NA, Pan, H, Haltiwanger, RS, Bellen, HJ

Cell 2008
20805998 Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells

Kong, D, Banerjee, S, Ahmad, A, Sethi, S, Sarkar, FH, Wang, Z, Li, Y

PLoS One 2010
10935626 Fringe is a glycosyltransferase that modifies Notch

Moloney, DJ, Panin, VM, Johnston, SH, Chen, J, Shao, L, Wilson, R, Wang, Y, Stanley, P, Irvine, KD, Haltiwanger, RS, Vogt, TF

Nature 2000
18347015 Roles of Pofut1 and O-fucose in mammalian Notch signaling

Stahl, M, Uemura, K, Ge, C, Shi, S, Tashima, Y, Stanley, P

J Biol Chem 2008
21602795 Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway

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

Nat Cell Biol 2011
11707585 Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1

Chen, J, Moloney, DJ, Stanley, P

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, Zhang, Y, Wang, L

J Biol Chem 2009
20080834 Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis

Hashimoto, Y, Akiyama, Y, Otsubo, T, Shimada, S, Yuasa, Y

Carcinogenesis 2010
9244302 Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane

Blaumueller, CM, Qi, H, Zagouras, P, Artavanis-Tsakonas, S

Cell 1997
9207795 Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila

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

Nat Genet 1997
10935637 Glycosyltransferase activity of Fringe modulates Notch-Delta interactions

Br├╝ckner, K, Perez, L, Clausen, H, Cohen, S

Nature 2000
20495621 Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment

Costa, FF, Seftor, EA, Bischof, JM, Kirschmann, DA, Strizzi, L, Arndt, K, de Fatima Bonaldo, M, Soares, MB, Hendrix, MJC

Epigenomics 2009
9187150 A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway

Johnston, SH, Rauskolb, C, Wilson, R, Prabhakaran, B, Irvine, KD, Vogt, TF

Development 1997
21551231 Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150

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

Blood 2011
19701457 Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2

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

PLoS One 2009
19714243 MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells

Ji, Q, Hao, X, Zhang, M, Tang, W, Meng, Y, Li, L, Xiang, D, DeSano, JT, Bommer, GT, Fan, D, Fearon, ER, Lawrence, TS, Xu, L

PLoS One 2009
19773441 MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes

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

Cancer Res 2009
11524432 Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase

Wang, Y, Shao, L, Shi, S, Harris, RJ, Spellman, MW, Stanley, P, Haltiwanger, RS

J Biol Chem 2001
9653148 The Notch1 receptor is cleaved constitutively by a furin-like convertase

Logeat, F, LeBail, O, Jarriault, S, Seidah, NG

Proc Natl Acad Sci U S A 1998
21490058 Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi

Fernandez-Valdivia, R, Takeuchi, H, Samarghandi, A, Lopez, M, Leonardi, J, Haltiwanger, RS, Jafar-Nejad, H

Development 2011
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