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Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell
H Katayama1, H Zhou, Q Li
1Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
STK15 is an Aurora/Ipl-1 related serine/threonine kinase that is associated with centrosomes and induces aneuploidy when overexpressed in mammalian cells. It is well known that phosphorylation and dephosphorylation of kinases are important for regulation of their activity. But mechanisms by which STK15 activity is regulated have not been elucidated. We report that STK15 contains two functional binding sites for protein phosphatase type 1 (PP1), and the binding of these proteins is cell cycle-regulated peaking at mitosis. Activated STK15 at mitosis phosphorylates PP1 and inhibits PP1 activity in vitro. In vivo, PP1 activity co-immunoprecipitated with STK15 is also reduced. These data indicate that STK15 inhibits PP1 activity during mitosis. Also, PP1 is shown to dephosphorylate active STK15 and abolish its activity in vitro. Furthermore, we show that non-binding mutants of STK15 for PP1 are superphosphorylated, but their kinase activities are markedly reduced. Cells transfected with these non-binding mutants manifest aberrant chromosome alignment during mitosis. Our results suggest that a feedback regulation through phosphorylation/dephosphorylation events between STK15 kinase and PP1 phosphatase operates through the cell cycle. Deregulation of this balance may contribute to anomalous segregation of chromosomes during mitotic progression of cancer cells.
Insights
STK15 kinase regulates protein phosphatase type 1 (PP1) activity during mitosis. This feedback loop ensures proper chromosome segregation, and its disruption may lead to cancer cell aneuploidy.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- STK15 (Aurora/Ipl-1 related kinase) is linked to centrosomes and aneuploidy.
- Kinase regulation via phosphorylation/dephosphorylation is crucial but STK15 regulation remains unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms of STK15 activity.
- To investigate the interaction between STK15 and protein phosphatase type 1 (PP1).
Main Methods:
- Identified functional binding sites for PP1 on STK15.
- Assessed cell cycle-regulated binding and activity assays (in vitro and in vivo).
- Utilized non-binding STK15 mutants for functional analysis.
Main Results:
- STK15 binds PP1 in a cell cycle-dependent manner, peaking at mitosis.
- Mitotic STK15 phosphorylates and inhibits PP1 activity; PP1 dephosphorylates and inactivates STK15.
- STK15-PP1 binding mutants show reduced kinase activity and aberrant chromosome alignment.
Conclusions:
- A feedback mechanism between STK15 and PP1 regulates kinase activity during the cell cycle.
- Disruption of this STK15-PP1 balance may contribute to chromosome missegregation in cancer cells.