Ubiquitination of DLL/JAG ligands upon binding to NOTCH2

Stable Identifier
Reaction [transition]
Homo sapiens
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NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH2 in trans. Integrity of the intracellular domain of DLL1 was shown to be essential for the successful release of NOTCH2 intracellular domain, NICD2, in response to DLL1 binding (Shimizu et al. 2002). 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). The pulling force model states that the endocytosis of ubiquitinated Notch ligands mechanically pulls 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). Using a cell-bead optical tweezers system to measure rupture force specific for cells expressing Dll1 bound to laser trapped Notch1 beads, it was shown that the mechanical force required for the activation of Notch signaling depends on ligand ubiquitination and subsequent clathrin-mediated endocytosis that involves dynamin, epsins and actin (Meloty-Kapella et al. 2012). Ligand endocytosis and recycling does not directly influence Dll1 and Notch1 interaction, except that it regulates the amount of ligand on the cell surface that is available to activate Notch (Shergill et al. 2012).

Literature References
PubMed ID Title Journal Year
16093323 The interplay between DSL proteins and ubiquitin ligases in Notch signaling

Delidakis, C, Pitsouli, C

Development 2005
22658936 Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin

Botvinick, E, Meloty-Kapella, L, Weinmaster, G, Shergill, B, Kuon, J

Dev. Cell 2012
11823422 Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain

Shimizu, K, Takahashi, T, Hirai, H, Kumano, K, Hamada, Y, Saito, T, Chiba, S

EMBO J 2002
15760269 Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila

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

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

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

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

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

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

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

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

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

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

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

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

Kim, CH, Ariza-McNaughton, L, Maust, D, Itoh, M, Jiang, YJ, Lorick, K, Wright, GJ, Yeo, SY, Weissman, AM, Chitnis, AB, Chandrasekharappa, SC, Lewis, J, Palardy, G, Oda, T

Dev Cell 2003
22658935 Optical tweezers studies on Notch: single-molecule interaction strength is independent of ligand endocytosis

Botvinick, E, Meloty-Kapella, L, Musse, AA, Weinmaster, G, Shergill, B

Dev. Cell 2012
18077452 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1

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

J Biol Chem 2008
Catalyst Activity

ubiquitin-protein transferase activity of MIB/NEURL [cytosol]

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