Regulation of Protein Phosphatase 1 by Phosphorylation

  • Zoe Lee

Student thesis: Phd

Abstract

Protein phosphorylation is a critical mechanism for regulating cellular function. The phosphorylation state of any protein is controlled by the antagonistic actions of kinases and phosphatases. Deregulated kinases have frequently been found to be oncogenic, resulting in the survival and spread of cancer cells. The vast body of research on kinases is not matched by our insight into the means by which the phosphatases counteract kinase activity. In human cells, >90% of serine/threonine phosphatase activity is regulated by protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). Humans express four isoforms of PP1 while S. pombe expresses two PP1 phosphatases known as Dis2 and Sds21. The core regions of PP1 are highly conserved, however, the unstructured C-terminal amino acid tails are highly divergent. All four mammalian isoforms of PP1 and S. pombe Dis2 contain a C- terminal TPPR motif which can be phosphorylated by Cdk1-Cyclin B to inhibit PP1 activity. I asked whether C-terminal phosphorylation may be a universal mode of PP1 control. To address this hypothesis, I focused on the Sds21 isoform in S. pombe which does not contain the conserved TPPR motif, but instead contains a phosphorylated DNA damage kinase consensus SQSS motif. Phosphorylation on the SQSS motif did not impact Sds21 activity, although it did alter the cellular distribution of Sds21 and was required for cell survival under DNA damage stress. Phosphorylation site mapping identified a novel phosphorylation event at a core conserved Cdk consensus site which resulted in the global degradation of Dis2. My studies have uncovered phosphorylation events which regulate PP1 localisation, protein levels and cell viability under DNA damage stress.
Date of Award31 Dec 2022
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorIain Hagan (Supervisor) & Claus Jorgensen (Supervisor)

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