Phosphorylation by Aurora B kinase regulates caspase-2 activity and function

Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploid due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cel...

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Bibliographic Details
Published in:Cell death and differentiation 2021-01, Vol.28 (1), p.349-366
Main Authors: Lim, Yoon, De Bellis, Dylan, Sandow, Jarrod J., Capalbo, Luisa, D’Avino, Pier Paolo, Murphy, James M., Webb, Andrew I., Dorstyn, Loretta, Kumar, Sharad
Format: Article
Language:English
Subjects:
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13/2
631/45/607/468
631/80/474
82/83
96
96/95
Apoptosis
Apoptosis - drug effects
Aurora B protein
Aurora Kinase B - genetics
Aurora Kinase B - metabolism
Biochemistry
Biomedical and Life Sciences
Caspase 2 - genetics
Caspase 2 - metabolism
Caspase-2
Cell Biology
Cell cycle
Cell Cycle Analysis
Cell Line, Tumor
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Humans
Kinases
Life Sciences
Mitosis
Mitosis - drug effects
Molecular modelling
Phosphorylation
Polyploidy
Protein Kinase Inhibitors - pharmacology
Stem Cells
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Summary:Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploid due to aberrant mitosis. Previous studies have demonstrated that the activation and catalytic function of caspase-2 are key steps in MC to trigger apoptosis and/or cell cycle arrest of mitotically defective cells. However, the molecular mechanisms that regulate caspase-2 activation and its function are unclear. Here, we identify six new phosphorylation sites in caspase-2 and show that a key mitotic kinase, Aurora B kinase (AURKB), phosphorylates caspase-2 at the highly conserved residue S384. We demonstrate that phosphorylation at S384 blocks caspase-2 catalytic activity and apoptosis function in response to mitotic insults, without affecting caspase-2 dimerisation. Moreover, molecular modelling suggests that phosphorylation at S384 may affect substrate binding by caspase-2. We propose that caspase-2 S384 phosphorylation by AURKB is a key mechanism that controls caspase-2 activation during mitosis.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-00604-y