The chromosomal passenger complex controls spindle checkpoint function independent from its role in correcting microtubule kinetochore interactions.
The chromosomal passenger complex (CPC) is a critical regulator of chromosome segregation during mitosis by correcting nonbipolar microtubule-kinetochore interactions. By severing these interactions, the CPC is thought to create unattached kinetochores that are subsequently sensed by the spindle assembly checkpoint (SAC) to prevent premature mitotic exit. We now show that spindle checkpoint function of the CPC and its role in eliminating nonbipolar attachments can be uncoupled. Replacing the chromosomal passenger protein INCENP with a mutant allele that lacks its coiled-coil domain results in an overt defect in a SAC-mediated mitotic arrest in response to taxol treatment, indicating that this domain is critical for CPC function in spindle checkpoint control. Surprisingly, this mutant could restore alignment and cytokinesis during unperturbed cell divisions and was capable of resolving syntelic attachments. Also, Aurora-B kinase was localized and activated normally on centromeres in these cells, ruling out a role for the coiled-coil domain in general Aurora-B activation. Thus, mere microtubule destabilization of nonbipolar attachments by the CPC is insufficient to install a checkpoint-dependent mitotic arrest, and additional, microtubule destabilization-independent CPC signaling toward the spindle assembly checkpoint is required for this arrest, potentially through amplification of the unattached kinetochore-derived checkpoint signal.
Vader
Gerben
G
Department of Medical Oncology, University Medical Center, 3584 CG Utrecht, The Netherlands.
Cruijsen
Carin W A
CW
van Harn
Tanja
T
Vromans
Martijn J M
MJ
Medema
René H
RH
Lens
Susanne M A
SM
D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases
J Cell Biol. 2000 Sep 4;150(5):975-88
10973989
J Cell Biol. 1998 Dec 28;143(7):1763-74
9864353
Curr Biol. 2000 Sep 7;10(17):1075-8
10996078
Exp Cell Res. 2001 Jan 15;262(2):122-7
11139336
Curr Biol. 2001 Jun 5;11(11):886-90
11516652
Genes Dev. 2001 Dec 1;15(23):3118-29
11731476
J Cell Biol. 2001 Dec 24;155(7):1147-57
11756469
Cell. 2002 Feb 8;108(3):317-29
11853667
Cell. 2002 Oct 18;111(2):163-72
12408861
Cell. 2003 Mar 21;112(6):751-64
12654243
J Cell Biol. 2003 Apr 28;161(2):281-94
12707311
J Cell Biol. 2003 Apr 28;161(2):267-80
12719470
EMBO J. 2003 Jun 16;22(12):2934-47
12805209
J Cell Sci. 2003 Jul 15;116(Pt 14):2987-98
12783991
Mol Biol Cell. 2003 Aug;14(8):3325-41
12925766
Science. 2003 Dec 19;302(5653):2120-4
14605209
Mol Cell. 2005 Apr 29;18(3):379-91
15866179
Nat Rev Cancer. 2005 Oct;5(10):773-85
16195750
Nat Cell Biol. 2006 Jan;8(1):78-83
16327780
EMBO Rep. 2006 Jan;7(1):85-92
16239925
EMBO J. 2006 Jan 11;25(1):45-57
16362039
Mol Biol Cell. 2006 Apr;17(4):1897-909
16436504
J Cell Biol. 2006 Jun 19;173(6):833-7
16769825
Cell. 2006 Dec 1;127(5):983-97
17129783
Cell. 2006 Dec 15;127(6):1179-91
17174893
Genes Dev. 2007 May 15;21(10):1163-8
17504936
Nat Cell Biol. 2004 Mar;6(3):232-7
14767480
Cell. 2004 Jul 23;118(2):187-202
15260989
J Cell Biol. 2004 Jul 19;166(2):179-91
15249581
J Cell Sci. 2004 Nov 1;117(Pt 23):5461-77
15509863
J Cell Biol. 1993 Oct;123(2):373-85
8408220
Nat Cell Biol. 2000 Sep;2(9):672-6
10980711