title: Regulated degradation of spindle assembly factors by the anaphase-promoting complex.
abstract: The ubiquitin ligase anaphase-promoting complex (APC/C) is essential for cell division in all eukaryotes. Loss of APC/C activity arrests cells at metaphase and results in severe aberrations of the mitotic spindle, but how the APC/C regulates spindle formation is not understood. Here, we report that the APC/C promotes the ubiquitination and degradation of four proteins required for Ran-dependent spindle assembly: Bard1, Hmmr, HURP, and NuSAP. Among these substrates, HURP and NuSAP can be degraded during spindle formation when the spindle checkpoint is active. Their degradation requires additional layers of regulation, and both SAFs are only degraded after being released from their inhibitor importin beta by Ran(GTP). Our findings reveal a tightly regulated mechanism by which the APC/C and the GTPase Ran control the abundance of active spindle assembly factors to achieve the accurate formation of the mitotic spindle.
authors.affiliation: Department of Molecular Cell Biology, University of California, Berkeley, 16 Barker Hall, Berkeley, CA 94720, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Michael
authors.initials: M
authors.lastname: Rape
mesh_terms: D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D028961:beta Karyopherins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: C465041:DLGAP5 protein, human; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D008869:Microtubule-Associated Proteins; C000709213:NUSAP1 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D028961:beta Karyopherins; C098946:hyaluronan-mediated motility receptor; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D020931:ran GTP-Binding Protein
references.citation: Mol Biol Cell. 2006 Jun;17(6):2646-60
references.pmid: 16571672
references.citation: EMBO J. 1998 Nov 16;17(22):6587-98
references.pmid: 9822603
references.citation: Nature. 2007 Apr 19;446(7138):921-5
references.pmid: 17443186
references.citation: J Cell Biol. 1999 Jan 25;144(2):213-24
references.pmid: 9922449
references.citation: Science. 2002 Mar 29;295(5564):2452-6
references.pmid: 11923538
references.citation: Nat Cell Biol. 2003 Oct;5(10):845-50
references.pmid: 14523392
references.citation: Science. 2005 Aug 26;309(5739):1373-6
references.pmid: 16123300
references.citation: Dev Cell. 2007 Jul;13(1):29-42
references.pmid: 17609108
references.citation: Curr Biol. 2004 Oct 26;14(20):1801-11
references.pmid: 15498487
references.citation: Cell. 2006 Nov 3;127(3):539-52
references.pmid: 17081976
references.citation: J Cell Biol. 2003 Sep 15;162(6):1017-29
references.pmid: 12963707
references.citation: Cancer Res. 2005 Feb 1;65(3):850-60
references.pmid: 15705883
references.citation: Curr Biol. 1999 Jul 1;9(13):680-9
references.pmid: 10395539
references.citation: Nat Genet. 2007 Nov;39(11):1338-49
references.pmid: 17922014
references.citation: Curr Biol. 2006 Apr 18;16(8):731-42
references.pmid: 16631580
references.citation: Cell. 2008 Jul 25;134(2):256-67
references.pmid: 18662541
references.citation: Nature. 2006 Mar 30;440(7084):697-701
references.pmid: 16572176
references.citation: EMBO J. 2003 Dec 15;22(24):6598-609
references.pmid: 14657031
references.citation: PLoS Genet. 2008 Jul 18;4(7):e1000126
references.pmid: 18797514
references.citation: Annu Rev Biochem. 2009;78:399-434
references.pmid: 19489725
references.citation: Cell. 2008 May 16;133(4):653-65
references.pmid: 18485873
references.citation: Cell. 2001 Jan 12;104(1):83-93
references.pmid: 11163242
references.citation: Nat Rev Mol Cell Biol. 2008 Jun;9(6):464-77
references.pmid: 18478030
references.citation: Curr Biol. 2007 Feb 6;17(3):230-6
references.pmid: 17276916
references.citation: Nature. 1986 Dec 18-31;324(6098):621
references.pmid: 3796729
references.citation: Mol Cell. 2002 Dec;10(6):1345-53
references.pmid: 12504010
references.citation: Curr Biol. 2006 Apr 18;16(8):743-54
references.pmid: 16631581
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):644-56
references.pmid: 16896351
references.citation: J Cell Biol. 2006 Jun 19;173(6):879-91
references.pmid: 16769820
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18213-8
references.pmid: 19822757
references.citation: Science. 2007 Apr 20;316(5823):417-21
references.pmid: 17412918
references.citation: Cell. 1995 Apr 21;81(2):261-8
references.pmid: 7736578
references.citation: Mol Biol Cell. 2008 May;19(5):2083-91
references.pmid: 18321990
references.citation: Cell Signal. 2007 Oct;19(10):2046-55
references.pmid: 17618083
references.citation: Cell. 2001 Jan 12;104(1):95-106
references.pmid: 11163243
references.citation: Chem Rev. 2009 Apr;109(4):1537-48
references.pmid: 19146381
references.citation: Mol Cell Biol. 2005 Dec;25(23):10516-27
references.pmid: 16287863
references.citation: Science. 2001 Jan 26;291(5504):653-6
references.pmid: 11229403
references.citation: J Cell Sci. 2008 May 15;121(Pt 10):1577-86
references.pmid: 18469014
references.citation: Oncogene. 2003 Jan 16;22(2):298-307
references.pmid: 12527899