The Saurin Lab is based in the School of Medicine, find out more about research in the Saurin Lab here.
Kinases and phosphatases work together in many different ways to control signalling outputs, including determination of the speed, amplitude, and localisation of a signalling response (1). In addition, kinases and phosphatases can also cooperate to drive rapid cycles of phosphorylation and dephosphorylation on individual molecules. The ability of phosphorylation sites to “flash” on and off in this way is something we know almost nothing about, and yet can determine key properties of a signal response (2). This studentship will study a bifunctional kinase-phosphatase module that has been conserved throughout evolution on a variety of different signalling complexes to drive such phosphorylation-dephosphorylation reactions.
The module consists of two adjacent phospho-dependent binding motifs that recruit either the kinase PLK1 or the phosphatase PP2A-B56. We recently identified this module on the BUB complex and demonstrated that it regulates the mitotic checkpoint response (3). It is similarly found on many other complexes, including the giant E3 ubiquitin ligase APC/C, where it controls E3 ligase activity and dynamics (4). The unique phospho-dependencies conferred by this module allows PLK1 to recruit PP2A, and PP2A to remove PLK1. Therefore, kinase and phosphatase are locked in a cycle of opposition that we believe drives continual phosphorylation-dephosphorylation reactions. The studentship will explore the mechanistic reason behind these cycles on different mitotic complexes.
The project will involve using cutting-edge approaches in cell biology, microscopy, synthetic biology and genome editing. These studies will be performed in close collaboration with the lab of Andrea Musacchio, Director of the Max Planck Institute Dortmund, who will help with relevant biochemical reconstitutions. The student will also use novel mass-spec technology that we developed recently, together with the group of Tony Ly in Dundee, to quantify the rates at which phosphorylation sites “flash” on and off within different complexes. These rates, which are a fundamental property of all phosphorylation sites, have never been quantified previously. The studentship provides a unique opportunity to study a fundamental signalling concept that is likely to have widespread functional relevance for many different processes.
1) Gelens L, Qian J, Bollen M, Saurin AT. The Importance of Kinase-Phosphatase Integration: Lessons from Mitosis. Trends Cell Biol. 2018 28:6-21.
2) Gelens L, Saurin AT. Exploring the Function of Dynamic Phosphorylation-Dephosphorylation Cycles. Dev Cell. 2018 44:659-663.
3) Cordeiro MH, Smith RJ, Saurin AT. Kinetochore phosphatases suppress autonomous Polo-like kinase 1 activity to control the mitotic checkpoint. J Cell Biol. 202 7:219:e202002020.
4) Fujimitsu K, Yamano H. Dynamic regulation of mitotic ubiquitin ligase APC/C by coordinated Plx1 kinase and PP2A phosphatase action on a flexible Apc1 loop. EMBO J. 2021 e107516.