title: Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta.
abstract: Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.
authors.affiliation: Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Gregory
authors.initials: G
authors.lastname: Palardy
authors.forename: Takaya
authors.initials: T
authors.lastname: Oda
authors.forename: Yun-Jin
authors.initials: YJ
authors.lastname: Jiang
authors.forename: Donovan
authors.initials: D
authors.lastname: Maust
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Yeo
authors.forename: Kevin
authors.initials: K
authors.lastname: Lorick
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
authors.forename: Linda
authors.initials: L
authors.lastname: Ariza-McNaughton
authors.forename: Allan M
authors.initials: AM
authors.lastname: Weissman
authors.forename: Julian
authors.initials: J
authors.lastname: Lewis
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.forename: Ajay B
authors.initials: AB
authors.lastname: Chitnis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D004705:Endocytosis; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008025:Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D015398:Signal Transduction; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D025801:Ubiquitin; D029961:Zebrafish Proteins; C064045:delta protein; D044767:Ubiquitin-Protein Ligases; C471932:mib1 protein, zebrafish; D008025:Ligases