Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta.
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.
Itoh
Motoyuki
M
Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD 20892, USA.
Kim
Cheol-Hee
CH
Palardy
Gregory
G
Oda
Takaya
T
Jiang
Yun-Jin
YJ
Maust
Donovan
D
Yeo
Sang-Yeob
SY
Lorick
Kevin
K
Wright
Gavin J
GJ
Ariza-McNaughton
Linda
L
Weissman
Allan M
AM
Lewis
Julian
J
Chandrasekharappa
Settara C
SC
Chitnis
Ajay B
AB
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*
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