Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1

Song, Ran; Koo, Bon–Kyoung; Yoon, Ki Jun; Yoon, Mi Jeong; Yoo, Kyeong Won; Kim, Hyun Taek; Oh, Hyeon Jeong; Kim, Yoon Young; Han, Jin Kwan; Kim, Cheol-Hee; Kong, Young Yun

doi:10.1074/jbc.m606601200

Cited by 50 publications

(69 citation statements)

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“…Its critical regulation of NotchDelta signaling alone incorporates it into almost every aspect of nervous system development (6,10,(55)(56)(57)(58)(59)(60). More recently, an interactome study revealed that it also plays a role in the equally vital Wnt signaling pathway (18).…”

Section: Discussionmentioning

confidence: 99%

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Mertz¹,

Tan

Pagala

et al. 2015

Molecular & Cellular Proteomics

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The mind bomb 1 (Mib1) ubiquitin ligase is essential for controlling metazoan development by Notch signaling and possibly the Wnt pathway. It is also expressed in postmitotic neurons and regulates neuronal morphogenesis and synaptic activity by mechanisms that are largely unknown. We sought to comprehensively characterize the Mib1 interactome and study its potential function in neuron development utilizing a novel sequential elution strategy for affinity purification, in which Mib1 binding proteins were eluted under different stringency and then quantified by the isobaric labeling method. The strategy identified the Mib1 interactome with both deep coverage and the ability to distinguish high-affinity partners from low-affinity partners. A total of 817 proteins were identified during the Mib1 affinity purification, including 56 high-affinity partners and 335 low-affinity partners, whereas the remaining 426 proteins are likely copurified contaminants or extremely weak binding proteins. The analysis detected all previously known Mib1-interacting proteins and revealed a large number of novel components involved in Notch and Wnt pathways, endocytosis and vesicle transport, the ubiquitin-proteasome system, cellular morphogenesis, and synaptic activities. Immunofluorescence studies further showed colocalization of Mib1 with five selected proteins: the Usp9x (FAM) deubiquitinating enzyme, alpha-, beta-, and delta-catenins, and CDKL5. Mutations of CDKL5 are associated with early infantile epileptic encephalopathy-2 (EIEE2), a severe form of mental retardation. We found that the expression of Mib1 downregulated the protein level of CDKL5 by ubiquitination, and antagonized CDKL5 function during the formation of dendritic spines. Thus, the sequential elution strategy enables biochemical characterization of protein interac-

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Section: Discussionmentioning

confidence: 99%

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Mertz¹,

Tan

Pagala

et al. 2015

Molecular & Cellular Proteomics

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“…In Drosophila, it is well established that the ubiquitin ligase activities of Neuralized and/or Mindbomb1 are needed for endocytosis, activation, and degradation of Notch ligands, all processes likely dependent on ubiquitination of the ligand intracellular domains (12,13,15,17,37). Furthermore, ectopic expression of a second murine Neur paralog, Neurl2, was shown to increase ubiquitination of Dll1 in transfected cells (22), and a Xenopus Neurl ortholog was shown to promote ubiquitination of in vitro translated Xenopus Delta1 (38). Nevertheless, until the present work it had not been rigorously demonstrated, using a purified enzyme system, that a Neuralized protein directly supports ubiquitination of a ligand.…”

Section: Discussionmentioning

confidence: 99%

“…□ S The on-line version of this article (available at http://www.jbc.org) contains supplemental ubiquitination in cells. In addition, Neurl2 functioned cooperatively with Mib1 to promote endocytosis of XDelta to Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate)-positive early endosomes (22); however, unequivocal evidence that Dll1 is a direct target of Neurl2 ubiquitin ligase activity is lacking. Although Neurl1 has also been shown to exhibit a nonspecific ubiquitin ligase activity in vitro (22), putative Neurl1 substrates have not been identified.…”

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confidence: 99%

“…In addition, Neurl2 functioned cooperatively with Mib1 to promote endocytosis of XDelta to Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate)-positive early endosomes (22); however, unequivocal evidence that Dll1 is a direct target of Neurl2 ubiquitin ligase activity is lacking. Although Neurl1 has also been shown to exhibit a nonspecific ubiquitin ligase activity in vitro (22), putative Neurl1 substrates have not been identified. In addition, whether Neurl1 plays a role in Notch signaling is unclear, because Neurl1 Ϫ/Ϫ mice exhibit no abnormal cell fate specifications during neurogenesis and somitogenesis, two processes in which Notch signaling has been shown to be involved (21,23).…”

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confidence: 99%

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Neuralized-like 1 (Neurl1) Targeted to the Plasma Membrane by N-Myristoylation Regulates the Notch Ligand Jagged1

Koutelou

Sato

Tomomori-Sato

et al. 2008

Journal of Biological Chemistry

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Notch signaling constitutes an evolutionarily conserved mechanism that mediates cell-cell interactions in various developmental processes. Numerous regulatory proteins interact with the Notch receptor and its ligands and control signaling at multiple levels. Ubiquitination and endocytosis followed by endosomal sorting of both the receptor and its ligands is essential for Notch-mediated signaling. The E3 ubiquitin ligases, Neuralized (Neur) and Mind Bomb (Mib1), are crucial for regulating the activity and stability of Notch ligands in Drosophila; however, biochemical evidence that the Notch ligands are directly targeted for ubiquitination by Neur and/or Mib1 has been lacking. In this report, we explore the function of Neurl1, a mouse ortholog of Drosophila Neur. We show that Neurl1 can function as an E3 ubiquitin ligase to activate monoubiquitination in vitro of Jagged1, but not other mammalian Notch ligands. Neurl1 expression decreases Jagged1 levels in cells and blocks signaling from Jagged1-expressing cells to neighboring Notchexpressing cells. We demonstrate that Neurl1 is myristoylated at its N terminus, and that myristoylation of Neurl1 targets it to the plasma membrane. Point mutations abolishing either Neurl1 myristoylation and plasma membrane localization or Neurl1 ubiquitin ligase activity impair its ability to down-regulate Jagged1 expression and to block signaling. Taken together, our results argue that Neurl1 at the plasma membrane can affect the signaling activity of Jagged1 by directly enhancing its ubiquitination and subsequent turnover.

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“…Two structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), are known to regulate the endocytosis of Notch ligands in Drosophila and zebrafish, respectively (16,17). In mammals, 2 Neur homologs, Neur1 (18,19) and Neur2 (20), and 2 Mib homologs, Mind bomb-1 (Mib1) (21) and Mib2 (22), have been identified. Although all 4 E3 ubiquitin ligases are known to induce the endocytosis of Notch ligands in vitro, only Mib1 has an obligatory role in the activation of Jag-as well as Dll-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable (23).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice

Jeong¹,

Jeon²,

Koo³

et al. 2009

J. Clin. Invest.

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108

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The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting, and a severe urinary concentrating defect manifested as nephrogenic diabetes insipidus. Histological analysis revealed a diminished number of principal cells and corresponding increase in the number of intercalated cells. Transgenic overexpression of Notch intracellular domain reversed the altered cellular composition of mutant renal collecting duct, with principal cells occupying the entire region. Our data demonstrate that Notch signaling is required for the development of the mammalian renal collecting duct and principal cell differentiation and indicate that pathway dysregulation may contribute to distal renal tubular disorders.

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Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1

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Cited by 50 publications

References 50 publications

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Neuralized-like 1 (Neurl1) Targeted to the Plasma Membrane by N-Myristoylation Regulates the Notch Ligand Jagged1

Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice

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