Aurora kinases are a family of serine/threonine protein kinases that play essential roles in mitosis and cytokinesis. AurB (Aurora B kinase) has shown a clear link to cancer and is being pursued as an attractive cancer target. Multiple small molecules targeting AurB have entered the clinic for the treatment of cancer. A protein cofactor, INCENP (inner centromere protein), regulates the cellular localization and activation of AurB. In the present study, we examined the effect of INCENP on the activation kinetics of AurB and also elucidated the kinetic mechanism of AurB-catalysed substrate phosphorylation. We have concluded that: (i) substoichoimetric concentrations of INCENP are sufficient for AurB autophosphorylation at the activation loop residue Thr232, and hence INCENP plays a catalytic role in AurB autophosphorylation; (ii) AurB/INCENP-catalysed phosphorylation of a peptide substrate proceeds through a rapid equilibrium random Bi Bi kinetic mechanism; and (iii) INCENP has relatively minor effects on the specific activity of AurB using a peptide substrate when compared with its role in AurB autoactivation. These results indicate that the effects of INCENP, and probably accessory proteins in general, may differ when enzymes are acting on different downstream targets.
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Research Article|
December 12 2008
The catalytic role of INCENP in Aurora B activation and the kinetic mechanism of Aurora B/INCENP
Jingsong Yang;
Jingsong Yang
1
*Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, U.S.A.
1Correspondence may be addressed to either of these authors (email jingsong.2.yang@gsk.com or zhihong.v.lai@gsk.com).
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Francesca Zappacosta;
Francesca Zappacosta
†Proteomics and Biological Mass Spectrometry Laboratory, GlaxoSmithKline, King of Prussia, PA 19406, U.S.A.
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Roland S. Annan;
Roland S. Annan
†Proteomics and Biological Mass Spectrometry Laboratory, GlaxoSmithKline, King of Prussia, PA 19406, U.S.A.
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Kelvin Nurse;
Kelvin Nurse
‡Biological Reagents and Assay Development, GlaxoSmithKline, King of Prussia, PA 19406, U.S.A.
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Peter J. Tummino;
Peter J. Tummino
*Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, U.S.A.
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Robert A. Copeland;
Robert A. Copeland
*Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, U.S.A.
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Zhihong Lai
Zhihong Lai
1
*Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, U.S.A.
1Correspondence may be addressed to either of these authors (email jingsong.2.yang@gsk.com or zhihong.v.lai@gsk.com).
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Publisher: Portland Press Ltd
Received:
July 11 2008
Revision Received:
August 26 2008
Accepted:
September 04 2008
Accepted Manuscript online:
September 04 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 417 (1): 355–360.
Article history
Received:
July 11 2008
Revision Received:
August 26 2008
Accepted:
September 04 2008
Accepted Manuscript online:
September 04 2008
Citation
Jingsong Yang, Francesca Zappacosta, Roland S. Annan, Kelvin Nurse, Peter J. Tummino, Robert A. Copeland, Zhihong Lai; The catalytic role of INCENP in Aurora B activation and the kinetic mechanism of Aurora B/INCENP. Biochem J 1 January 2009; 417 (1): 355–360. doi: https://doi.org/10.1042/BJ20081365
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