Pre-NOTCH Processing in Golgi

Stable Identifier
Homo sapiens
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NOTCH undergoes final posttranslational processing in the Golgi apparatus (Lardelli et al. 1994, Blaumueller et al. 1997, Weinmaster et al. 1991, Weinmaster et al. 1992, Uyttendaele et al. 1996). Movement of NOTCH precursors from the endoplasmic reticulum to Golgi is controlled by SEL1L protein, a homolog of C. elegans sel-1. SEL1L localizes to the endoplasmic reticulum membrane and prevents translocation of misfolded proteins, therefore serving as a quality control check (Li et al. 2010, Sundaram et al. 1993, Francisco et al. 2010). Similarly, C. elegans sel-9 and its mammalian homolog TMED2 are Golgi membrane proteins that participate in quality control of proteins transported from Golgi to the plasma membrane. Translocation of a mutant C. elegans NOTCH homolog lin-12 from the Golgi to the plasma membrane is negatively regulated by sel-9 (Wen et al. 1999). A GTPase RAB6 positively controls NOTCH trafficking through Golgi (Purcell et al. 1999).

Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009).

An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2.
Literature References
PubMed ID Title Journal Year
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
1764995 A homolog of Drosophila Notch expressed during mammalian development

Roberts, VJ, Lemke, G, Weinmaster, G

Development 1991
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
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
8681805 Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene

Wu, G, Marazzi, G, Uyttendaele, H, Kitajewski, J, Yan, Q, Sassoon, D

Development 1996
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
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
20170518 SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells

Francisco, AB, Long, Q, Schimenti, JC, Munroe, RJ, Li, S

BMC Dev Biol 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
8293978 Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans

Greenwald, I, Sundaram, M

Genetics 1993
7918097 The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium

Dahlstrand, J, Lendahl, U, Lardelli, M

Mech Dev 1994
20197277 Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality

Singh, R, Francisco, AB, Long, Q, Yang, L, Schimenti, JC, Munroe, RJ, Qi, L, Biunno, I, Vani, AK, Cardano, M, Li, S, Diaferia, G

J Biol Chem 2010
10935637 Glycosyltransferase activity of Fringe modulates Notch-Delta interactions

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

Nature 2000
10459009 The developmental role of warthog, the notch modifier encoding Drab6

Artavanis-Tsakonas, S, Purcell, K

J Cell Biol 1999
11135303 Oh no, Notch again!

Lendahl, U, Frisen, J

Bioessays 2001
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
10366590 p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans

Wen, C, Greenwald, I

J Cell Biol 1999
1295745 Notch2: a second mammalian Notch gene

Roberts, VJ, Lemke, G, Weinmaster, G

Development 1992
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