Ubiquitination of DLL/JAG ligands upon binding to NOTCH1

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R-HSA-1980074
Type
Reaction [transition]
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
15760269 Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila

Le Borgne, R, Remaud, S, Hamel, S, Schweisguth, F

PLoS Biol 2005
16093323 The interplay between DSL proteins and ubiquitin ligases in Notch signaling

Pitsouli, C, Delidakis, C

Development 2005
18043734 An obligatory role of mind bomb-1 in notch signaling of mammalian development

Koo, BK, Yoon, MJ, Yoon, KJ, Im, SK, Kim, YY, Kim, CH, Suh, PG, Jan, YN, Kong, YY

PLoS One 2007
15824097 Mind bomb-2 is an E3 ligase for Notch ligand

Koo, BK, Yoon, KJ, Yoo, KW, Lim, HS, Song, R, So, JH, Kim, CH, Kong, YY

J Biol Chem 2005
11740940 Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta

Lai, EC, Deblandre, GA, Kintner, C, Rubin, GM

Dev Cell 2001
15829515 The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta

Lai, EC, Roegiers, F, Qin, X, Jan, YN, Rubin, GM

Development 2005
17003037 Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1

Song, R, Koo, BK, Yoon, KJ, Yoon, MJ, Yoo, KW, Kim, HT, Oh, HJ, Kim, YY, Han, JK, Kim, CH, Kong, YY

J Biol Chem 2006
12530964 Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta

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

Dev Cell 2003
18077452 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1

Koutelou, E, Sato, S, Tomomori-Sato, C, Florens, LA, Swanson, SK, Washburn, MP, Kokkinaki, M, Conaway, RC, Conaway, JW, Moschonas, NK

J Biol Chem 2008
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Title
ubiquitin-protein transferase activity of MIB/NEURL [cytosol]
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