Notch1 signaling is mediated by importins alpha 3, 4, and 7.
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.
Huenniger
Kerstin
K
Leibniz Institute for Age Research, Fritz Lipmann Institute, Beutenbergstr. 11, 07745, Jena, Germany.
Krämer
Andreas
A
Soom
Malle
M
Chang
Iree
I
Köhler
Matthias
M
Depping
Reinhard
R
Kehlenbach
Ralph H
RH
Kaether
Christoph
C
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*
D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D028901:alpha Karyopherins
Nat Genet. 1992 Dec;2(4):343
1303292
Cell. 1996 Sep 20;86(6):985-94
8808633
J Biol Chem. 2006 Mar 24;281(12):7890-8
16434391
Nature. 1998 May 28;393(6683):382-6
9620803
Cell. 2009 Apr 17;137(2):216-33
19379690
FEBS Lett. 2008 May 28;582(12):1693-9
18440314
J Immunol. 2001 Jul 1;167(1):289-95
11418662
Mol Cell Biol. 1999 Nov;19(11):7782-91
10523667
Cancer Lett. 2007 Sep 18;255(1):117-26
17513037
Traffic. 2005 Mar;6(3):173-86
15702986
Mol Biol Cell. 1997 Jun;8(6):945-56
9201707
J Cell Biol. 1996 Aug;134(3):589-601
8707840
Mol Cell Biol. 2001 Sep;21(17):6071-9
11486044
J Clin Invest. 2009 Jan;119(1):169-81
19104151
Eur J Cell Biol. 2001 Nov;80(11):669-77
11824786
Mol Cell Biol. 2004 Dec;24(23):10246-55
15542834
Development. 2005 Apr;132(8):1751-62
15790962
J Biol Chem. 2007 Feb 23;282(8):5101-5
17170104
Nat Cell Biol. 2007 Jan;9(1):72-9
17159997
Dev Biol. 2002 Apr 15;244(2):396-406
11944946
Mol Biol Cell. 2008 May;19(5):2300-10
18305100
Trends Cell Biol. 2004 Sep;14(9):505-14
15350979
Mol Cell Biol. 2000 Jun;20(11):3928-41
10805736
J Cell Physiol. 2009 Jan;218(1):84-93
18727102
J Biol Chem. 1997 Apr 25;272(17):11336-43
9111040
Nature. 2009 Apr 23;458(7241):987-92
19363474
Dev Neurosci. 2006;28(1-2):118-27
16508309
Development. 1994 Sep;120(9):2385-96
7956819
J Cell Sci. 1997 Jul;110 ( Pt 13):1453-63
9224763
Science. 1999 Apr 30;284(5415):770-6
10221902
J Biol Chem. 2003 Sep 5;278(36):34427-37
12826675
J Biol Chem. 2007 Sep 21;282(38):27685-92
17652081
Methods Enzymol. 1995;257:279-91
8583930
Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89
16921404
Genome Biol. 2006;7(10):R100
17076895