title: Rabconnectin-3 is a functional regulator of mammalian Notch signaling.
abstract: The Notch signaling pathway is important for cell fate decisions in embryonic development and adult life. Defining the functional importance of the Notch pathway in these contexts requires the elucidation of essential signal transduction components that have not been fully characterized. Here, we show that Rabconnectin-3B is required for the Notch pathway in mammalian cells. siRNA-mediated silencing of Rabconnectin-3B in mammalian cells attenuated Notch signaling and disrupted the activation and nuclear accumulation of the Notch target Hes1. Rabconnectin-3B knockdown also disrupted V-ATPase activity in mammalian cells, consistent with previous observations in Drosophila. Pharmacological inhibition of the V-ATPase complex significantly reduced Notch signaling in mammalian cells. Finally, Rabconnectin-3B knockdown phenocopied functional disruption of Notch signaling during osteoclast differentiation. Collectively, these findings define an important role for Rabconnectin-3 and V-ATPase activity in the Notch signaling pathway in mammalian cells.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Nilay
authors.initials: N
authors.lastname: Sethi
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Debra
authors.initials: D
authors.lastname: Quek
authors.forename: Trudi
authors.initials: T
authors.lastname: Schupbach
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D025262:Vacuolar Proton-Translocating ATPases; C452848:DMXL2 protein, human; C489734:Hes1 protein, mouse; C078493:HES1 protein, human
references.citation: EMBO Rep. 2003 Dec;4(12):1163-8
references.pmid: 14608370
references.citation: Nat Cell Biol. 2001 Apr;3(4):384-91
references.pmid: 11283612
references.citation: J Biol Chem. 2008 Mar 7;283(10):6509-18
references.pmid: 18156632
references.citation: J Biol Chem. 2002 Apr 19;277(16):13831-9
references.pmid: 11844802
references.citation: Blood. 2003 Mar 15;101(6):2227-34
references.pmid: 12411305
references.citation: Development. 2010 Jun;137(11):1825-32
references.pmid: 20460366
references.citation: Nat Genet. 2003 Mar;33(3):416-21
references.pmid: 12590261
references.citation: Curr Biol. 2004 Dec 29;14(24):2237-44
references.pmid: 15620650
references.citation: Dev Cell. 2009 Sep;17(3):387-402
references.pmid: 19758563
references.citation: Cancer Sci. 2009 Aug;100(8):1460-7
references.pmid: 19459857
references.citation: Biochem Biophys Res Commun. 2009 May 1;382(2):451-6
references.pmid: 19289106
references.citation: J Cell Biol. 2004 Jul 5;166(1):73-83
references.pmid: 15240571
references.citation: Mol Cell Biol. 2008 Oct;28(20):6402-12
references.pmid: 18710934
references.citation: Curr Opin Genet Dev. 2009 Aug;19(4):323-8
references.pmid: 19447603
references.citation: Oncogene. 2008 Sep 1;27(38):5124-31
references.pmid: 18758481
references.citation: J Cell Biol. 2009 Mar 9;184(5):621-9
references.pmid: 19255248
references.citation: Cancer Cell. 2005 Jul;8(1):13-23
references.pmid: 16023595
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):171-9
references.pmid: 18342499
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: Cancer Cell. 2009 Jul 7;16(1):55-66
references.pmid: 19573812
references.citation: J Clin Invest. 1996 Feb 1;97(3):761-8
references.pmid: 8609233
references.citation: Dev Cell. 2009 May;16(5):633-47
references.pmid: 19460341
references.citation: Ann N Y Acad Sci. 2010 Mar;1192:257-68
references.pmid: 20392245
references.citation: J Cell Biol. 2008 Feb 25;180(4):755-62
references.pmid: 18299346
references.citation: Development. 2004 Mar;131(5):965-73
references.pmid: 14973298
references.citation: Cancer Cell. 2003 Jun;3(6):537-49
references.pmid: 12842083