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Title: Protein phosphatase 6 function and regulation throughout the cell cycle
Author: Ahel, Josip
ISNI:       0000 0004 7654 2607
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Faithful cell division is a basic requirement for the generation of all living cells. Essential to this task is the correct formation and maintenance of bipolar mitotic spindles, which segregate the duplicated genome in mitosis. This process is dependent on the balanced and concerted activities of Aurora A and PLK1 kinases. Integration of function between these two kinases is partially explained by Aurora Amediated activation of PLK1. Further regulation is conferred by the heterotrimeric protein phosphatase 6 (PP6), which counteracts Aurora A autoactivation. How the activity of this phosphatase is regulated in space and time remains poorly understood. The results presented here demonstrate that PP6 is functionally stratified into three distinct pools based on the regulatory SAPS subunit, which confers binding-mediated substrate specificity. This property allows only PP6-SAPS2 and PP6-SAPS3 to dephosphorylate Aurora A. Furthermore, SAPS subunits confer unique regulatory properties to the holoenzyme. Uniquely, PLK1 binds to and phosphorylates PP6-SAPS2 in mitosis, inhibiting its activity against Aurora A. The combined action of PP6-SAPS2 and the constitutively active PP6-SAPS3 establishes feedback control between PLK1 and Aurora A activation during mitosis, and during a G2 DNA damage checkpoint. Concordantly, PP6 is important for normal cell cycle progression in non-transformed cells. Thus, this work firmly establishes the features conferring specific properties to PP6 holoenzymes and uncovers the first known mechanism of PP6 activity regulation.
Supervisor: Barr, Francis ; Gruneberg, Ulrike Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry ; Cell biology