title: Notch1 signaling is mediated by importins alpha 3, 4, and 7.
abstract: The Notch signaling pathway is an important regulation system for the development and self-renewal of different tissues. A specific feature of this signaling cascade is the function of Notch as a surface receptor and regulator of gene expression. Hence, Notch activation and signal transduction requires the proteolytic release of the Notch intracellular domain (NICD), which activates the transcription of cell-specific genes after its transport into the nucleus. To date, little is known about the mechanisms that mediate NICD nuclear import. We here show that transport of NICD into the nucleus is mediated by the canonical importin alpha/beta1 pathway. GST pull-down experiments revealed that NICD binds via one of its four potential nuclear localization signals to importins alpha3, alpha4, and alpha7, but not to alpha1 and alpha5. siRNA-mediated knockdown experiments showed that importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of NICD and thus are directly involved in Notch signaling.
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Beutenbergstr. 11, 07745, Jena, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Huenniger
authors.forename: Andreas
authors.initials: A
authors.lastname: Krämer
authors.forename: Malle
authors.initials: M
authors.lastname: Soom
authors.forename: Iree
authors.initials: I
authors.lastname: Chang
authors.forename: Matthias
authors.initials: M
authors.lastname: Köhler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Kehlenbach
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaether
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D032446:Myoblasts / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D028901:alpha Karyopherins
references.citation: Nat Genet. 1992 Dec;2(4):343
references.pmid: 1303292
references.citation: Cell. 1996 Sep 20;86(6):985-94
references.pmid: 8808633
references.citation: J Biol Chem. 2006 Mar 24;281(12):7890-8
references.pmid: 16434391
references.citation: Nature. 1998 May 28;393(6683):382-6
references.pmid: 9620803
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690
references.citation: FEBS Lett. 2008 May 28;582(12):1693-9
references.pmid: 18440314
references.citation: J Immunol. 2001 Jul 1;167(1):289-95
references.pmid: 11418662
references.citation: Mol Cell Biol. 1999 Nov;19(11):7782-91
references.pmid: 10523667
references.citation: Cancer Lett. 2007 Sep 18;255(1):117-26
references.pmid: 17513037
references.citation: Traffic. 2005 Mar;6(3):173-86
references.pmid: 15702986
references.citation: Mol Biol Cell. 1997 Jun;8(6):945-56
references.pmid: 9201707
references.citation: J Cell Biol. 1996 Aug;134(3):589-601
references.pmid: 8707840
references.citation: Mol Cell Biol. 2001 Sep;21(17):6071-9
references.pmid: 11486044
references.citation: J Clin Invest. 2009 Jan;119(1):169-81
references.pmid: 19104151
references.citation: Eur J Cell Biol. 2001 Nov;80(11):669-77
references.pmid: 11824786
references.citation: Mol Cell Biol. 2004 Dec;24(23):10246-55
references.pmid: 15542834
references.citation: Development. 2005 Apr;132(8):1751-62
references.pmid: 15790962
references.citation: J Biol Chem. 2007 Feb 23;282(8):5101-5
references.pmid: 17170104
references.citation: Nat Cell Biol. 2007 Jan;9(1):72-9
references.pmid: 17159997
references.citation: Dev Biol. 2002 Apr 15;244(2):396-406
references.pmid: 11944946
references.citation: Mol Biol Cell. 2008 May;19(5):2300-10
references.pmid: 18305100
references.citation: Trends Cell Biol. 2004 Sep;14(9):505-14
references.pmid: 15350979
references.citation: Mol Cell Biol. 2000 Jun;20(11):3928-41
references.pmid: 10805736
references.citation: J Cell Physiol. 2009 Jan;218(1):84-93
references.pmid: 18727102
references.citation: J Biol Chem. 1997 Apr 25;272(17):11336-43
references.pmid: 9111040
references.citation: Nature. 2009 Apr 23;458(7241):987-92
references.pmid: 19363474
references.citation: Dev Neurosci. 2006;28(1-2):118-27
references.pmid: 16508309
references.citation: Development. 1994 Sep;120(9):2385-96
references.pmid: 7956819
references.citation: J Cell Sci. 1997 Jul;110 ( Pt 13):1453-63
references.pmid: 9224763
references.citation: Science. 1999 Apr 30;284(5415):770-6
references.pmid: 10221902
references.citation: J Biol Chem. 2003 Sep 5;278(36):34427-37
references.pmid: 12826675
references.citation: J Biol Chem. 2007 Sep 21;282(38):27685-92
references.pmid: 17652081
references.citation: Methods Enzymol. 1995;257:279-91
references.pmid: 8583930
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89
references.pmid: 16921404
references.citation: Genome Biol. 2006;7(10):R100
references.pmid: 17076895