1. Phosphorylation by Aurora B kinase regulates caspase-2 activity and function
- Author
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Luisa Capalbo, Jarrod J. Sandow, Yoon Lim, James M. Murphy, Loretta Dorstyn, Andrew I. Webb, Dylan De Bellis, Sharad Kumar, Pier Paolo D'Avino, Lim, Yoon [0000-0003-1110-1969], De Bellis, Dylan [0000-0002-2741-7004], Sandow, Jarrod J. [0000-0001-5684-8236], D’Avino, Pier Paolo [0000-0002-4773-6950], Murphy, James M. [0000-0003-0195-3949], Webb, Andrew I. [0000-0001-5061-6995], Kumar, Sharad [0000-0001-7126-9814], Apollo - University of Cambridge Repository, Sandow, Jarrod J [0000-0001-5684-8236], D'Avino, Pier Paolo [0000-0002-4773-6950], Murphy, James M [0000-0003-0195-3949], Webb, Andrew I [0000-0001-5061-6995], Lim, Yoon, De Bellis, Dylan, Sandow, Jarrod J, Capalbo, Luisa, D'Avino, Pier Paolo, Murphy, James M, Webb, Andrew I, Dorstyn, Loretta, and Kumar, Sharad
- Subjects
Cell cycle checkpoint ,Caspase 2 ,Aurora B kinase ,96 ,Mitosis ,Apoptosis ,13 ,96/95 ,Dephosphorylation ,mitotic catastrophe (MC) ,13/2 ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Aurora Kinase B ,Humans ,Phosphorylation ,Molecular Biology ,Mitotic catastrophe ,Protein Kinase Inhibitors ,82/83 ,030304 developmental biology ,631/80/474 ,0303 health sciences ,biology ,Chemistry ,phosphorylation ,article ,Proteases ,Cell Biology ,631/45/607/468 ,Cell biology ,Cysteine Endopeptidases ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,caspase-2 catalytic activity ,Function (biology) ,Cytokinesis - Abstract
Mitotic catastrophe (MC) is an important oncosuppressive mechanism that serves to eliminate cells that become polyploid or aneuploidy 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.
- Published
- 2020