Mind Bomb-2 Is an E3 Ligase for Notch Ligand

Koo, Bon–Kyoung; Yoon, Ki‐Jun; Yoo, Kyeong Won; Lim, Hyoung Soo; Song, Ran; So, Ju Hoon; Kim, Cheol‐Hee; Kong, Young Yun

doi:10.1074/jbc.m501631200

Cited by 95 publications

(119 citation statements)

References 39 publications

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“…Skeletrophin, and its paralogue, mind bomb (also reported as DIP-1 (Jin et al, 2002) or mind bomb-1 (Koo et al, 2005b), target the intracellular region of Notch ligands and mediates ligand-dependent Notch activation. Internalization of Notch ligands followed by ubiquitination by skeletrophin and mind bomb is critical for Notch signal transduction (Itoh et al, 2003;Koo et al, 2005a, b;Pitsouli and Delidakis, 2005;Takeuchi et al, 2005;Wang and Struhl, 2005).…”

Section: Discussionmentioning

confidence: 99%

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

et al. 2006

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Section: Discussionmentioning

confidence: 99%

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

et al. 2006

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“…In the case of the EGF receptor, mutation of multiple intracellular lysines within the kinase domain of the protein leads to an almost complete loss of EGF receptor ubiquitination but did not result in the decrease of its internalization rate (16). Regarding Notch ligands, it has been shown that the E3 ligase Mind Bomb 1 promotes ubiquitination and internalization of mammalian Dll1 (17). It has also been reported that to be active, Drosophila Delta has to traffic through a Neur/Mib-and epsin-dependent pathway, although the majority of Delta molecules traffic in a nonproductive manner through a different pathway, which is ubiquitination-dependent but epsin-independent and may lead to degradation (18).…”

Section: Several Authors Have Reported That Ubiquitination and Endocymentioning

confidence: 99%

The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity

Heuss

Ndiaye‐Lobry

Six

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

116

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Genetic studies have shown that ubiquitination and endocytosis of the Drosophila ligand Delta in signal-sending cells are required for activation of Notch signaling, but how these events promote Notch activation remains poorly understood. Here, we show that an ubiquitination-defective mutant of the murine Delta-homologue Dll1 is endocytosed but, in contrast to the wild-type Dll1, is unable to subsequently recycle back to the cell surface or to bind Notch1 efficiently. These results demonstrate that ubiquitination, although not required for endocytosis, is essential for Dll1 recycling and that recycling is required to acquire affinity for the receptor. On the other hand, a chimeric molecule encompassing the extracellular domain of Dll1 and the transmembrane/intracellular domain of Dll3, which contains no lysine, is endocytosed, recycled, and interacts with Notch1 but is unable to induce transendocytosis of the extracellular region of Notch1 or to signal. These observations suggest that the chimera uses an ubiquitination-independent signal to recycle, allowing it to acquire affinity for Notch1. Our results support the idea that ligand recycling determines its competence to bind efficiently to the receptor but that this is insufficient to allow it to perform transendocytosis, an event required for activation of Notch signaling. Finally, the present study indicates that Dll1 partially localizes to lipid microdomains, whereas both ubiquitination-defective Dll1 and the Dll1-3 chimera are excluded from these compartments, suggesting that these microdomains provide the environment necessary for Dll1 to activate Notch signaling.ubiquitination ͉ recycling ͉ transendocytosis ͉ membrane microdomains

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“…1). Three of these colonies contained plasmids encoding the RING finger domain of Mib2, a protein that has previously been reported to have E3 ubiquitin ligase activity (37). Because of the recently identified role of the UPS in activity-dependent regulation of excitatory synaptic proteins (28 -30), we were interested in further characterizing whether Mib2 was a phosphorylation-dependent NR2B-interacting protein.…”

Section: Mib2 Interacts With the Nr2b Cytoplasmic Tail In A Fyn-depenmentioning

confidence: 99%

“…Mib2 Ubiquitinates NR2B in a Fyn Phosphorylation-dependent Manner-Mib2 is known to have intrinsic E3 ubiquitin ligase activity (37). To test whether the NR2B subunit is a substrate for Mib2, we performed ubiquitination assays.…”

Section: Mib2 Colocalizes With Nmdars Inmentioning

confidence: 99%

Mind Bomb-2 Is an E3 Ligase That Ubiquitinates the N-Methyl-d-aspartate Receptor NR2B Subunit in a Phosphorylation-dependent Manner

Jurd¹,

Thornton²,

Wang

et al. 2008

Journal of Biological Chemistry

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The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity. Post-translational modifications of NMDARs, such as phosphorylation, alter both the activity and trafficking properties of NMDARs. Ubiquitination is increasingly being recognized as another post-translational modification that can alter synaptic protein composition and function. We identified Mind bomb-2 as an E3 ubiquitin ligase that interacts with and ubiquitinates the NR2B subunit of the NMDAR in mammalian cells. The protein-protein interaction and the ubiquitination of the NR2B subunit were found to be enhanced in a Fyn phosphorylation-dependent manner. Immunocytochemical studies reveal that Mind bomb-2 is localized to postsynaptic sites and colocalizes with the NMDAR in apical dendrites of hippocampal neurons. Furthermore, we show that NMDAR activity is down-regulated by Mind bomb-2. These results identify a specific E3 ubiquitin ligase as a novel interactant with the NR2B subunit and suggest a possible mechanism for the regulation of NMDAR function involving both phosphorylation and ubiquitination.The N-methyl-D-aspartate receptors (NMDARs) 4 are glutamate-gated ion channels that are important in synaptic plasticity events in the mammalian brain, and are comprised of an obligatory NR1 subunit and modulatory NR2 (A-D) or NR3 subunits (1). While the NR1 subunit has a short intracellular tail, the NR2 subunits have large intracellular C-terminal tails that directly interact with proteins that play essential roles in the regulation of NMDAR function (2, 3).The intracellular domains of NMDAR subunits are phosphorylated by a number of protein kinases. For example, Src-family protein-tyrosine kinases (PTKs), such as Src and Fyn, phosphorylate specific tyrosine sites within the NR2A and NR2B intracellular tails (4 -7), and this positively modulates channel function (5, 7-12). Tyrosine phosphorylation of the NR2 subunits of the NMDAR is enhanced under a number of synaptic plasticityrelated events, including long-term potentiation (LTP) (13-15), fear-related learning (16), exposure to alcohol (17-19), and ischemia (20).Tyrosine phosphorylation also positively regulates the trafficking of NMDARs from intracellular compartments to the postsynaptic density (PSD) (10, 12), the stability of NMDARs at the synaptic membrane (21, 22) and controls the association of the NMDAR with spectrin (23). Tyrosine phosphorylation can also influence which proteins bind to the receptor. For example, phosphatidylinositol 3-kinase (PI 3-kinase), and phospholipase C-␥ (PLC-␥) bind to NR2 subunits in a tyrosine phosphorylation-dependent manner (24,25), and the increased association of PI 3-kinase with phosphorylated NMDARs has been suggested to contribute to altered signaling in the hippocampus after ischemia (20). Thus, tyrosine phosphorylation plays an essential role in both the regulation of NMDAR channel activity and NMDAR-mediated downstream signaling cascades.In addition to phosphorylation, ubiquitination is another post-translational modificatio...

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Mind Bomb-2 Is an E3 Ligase for Notch Ligand

Cited by 95 publications

References 39 publications

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion

The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity

Mind Bomb-2 Is an E3 Ligase That Ubiquitinates the N-Methyl-d-aspartate Receptor NR2B Subunit in a Phosphorylation-dependent Manner

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