Reactome | Pre-NOTCH Processing in Golgi

Pre-NOTCH Processing in Golgi

Stable Identifier

R-HSA-1912420

Type

Pathway

Species

Homo sapiens

Compartment

Golgi membrane, endoplasmic reticulum membrane, Golgi lumen, plasma membrane

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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
1295745	Notch2: a second mammalian Notch gene Roberts, VJ, Lemke, G, Weinmaster, G	Development	1992
10366590	p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans Wen, C, Greenwald, I	J Cell Biol	1999
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
11135303	Oh no, Notch again! Lendahl, U, Frisen, J	Bioessays	2001
10459009	The developmental role of warthog, the notch modifier encoding Drab6 Artavanis-Tsakonas, S, Purcell, K	J Cell Biol	1999
10935637	Glycosyltransferase activity of Fringe modulates Notch-Delta interactions Brückner, K, Cohen, S, Perez, L, Clausen, H	Nature	2000
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
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
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
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
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
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
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
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
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
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
1764995	A homolog of Drosophila Notch expressed during mammalian development Roberts, VJ, Lemke, G, Weinmaster, G	Development	1991
9727485	Roles for proteolysis and trafficking in notch maturation and signal transduction Jan, YN, Chan, YM	Cell	1998
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