title: Numb regulates Notch1, but not Notch3, during myogenesis.
abstract: In the vertebrate embryo, skeletal muscle is derived from the myotome of the somites. Notch1-3 demonstrate overlapping and distinct expression patterns in mouse somites. Notch1 and Notch2 have been shown to be inhibitors of skeletal myogenesis. The current data demonstrate that Notch3 also is an effective inhibitor of MyoD induced myogenesis. Numb, an adaptor protein that promotes Notch degradation by recruiting the E3 ubiquitin ligase, Itch, is limited in expression to dividing cells of the dorsal medial lip of the dermomyotome and the myotome itself. Here the specificity of the four protein isoforms of Numb for the Notch receptors was examined. In transcription and myogenic differentiation assays, Notch1 was consistently negatively regulated by all four Numb isoforms, and Notch3 was not a target for Numb. Notch2 however was variably affected. Subsequent analyses showed that unlike Notch1, that Notch3 was not polyubiquitinated, nor degraded when co-expressed in cells with Numb. These data provide the first observations that Notch receptors are variably affected by Numb and will be important for the interpretation of the function of Notch and Numb interactions during the development of many different cells and tissues.
authors.affiliation: Biology Graduate Program, School of Life Sciences, Arizona State University, Tempe, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Beres
authors.forename: Rajani
authors.initials: R
authors.lastname: George
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lougher
authors.forename: Michael
authors.initials: M
authors.lastname: Barton
authors.forename: Brian C
authors.initials: BC
authors.lastname: Verrelli
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
authors.forename: J Alan
authors.initials: JA
authors.lastname: Rawls
authors.forename: Jeanne
authors.initials: J
authors.lastname: Wilson-Rawls
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D017930:Genes, Reporter; D047468:Immunoprecipitation; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics*; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D015533:Transcriptional Activation; D054875:Ubiquitination
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; C106293:Numb protein, mouse; D010446:Peptide Fragments; D020033:Protein Isoforms; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D008156:Luciferases