New insights into control of core cell regulatorCertain cell components are part of many cell processes and do different roles depending on where they are in the cell and what other molecules are nearby. These multifunctional components are often critical to cell survival because they do so many things. Protein phosphatase 2A (PP2A) is one of these key regulators, with widespread effects in many different cell types. Various studies have highlighted the role of PP2A in controlling cell growth, division and signalling, and changes to PP2A have been implicated in diseases including cancer and Alzheimer’s disease.
A new study, including scientists from the Le Novère lab in the Signalling Programme and published in the journal eLife, has expanded the complex web of molecules that influence the activity of PP2A to include two further proteins, ARPP-16 and MAST3. These proteins have previously been shown to aid brain cell communication via a chemical signal called dopamine. The work, led by Professor Angus Nairn from Yale University, shows that MAST3 activates ARPP-16, which in turn shuts down PP2A. These proteins are found in many living things and provide a connection between crucial signalling systems inside cells and PP2A as a core cell regulator.
Cells use many small chemical signals to communicate and to carry information about their surroundings and environment. Many systems are involved in collecting this information and a chemical called cAMP forms part of many of them. As such, the amount of available cAMP can be important in indicating to a cell how it should respond to its environment.
High levels of cAMP activate a protein called PKA, which is able to turn many other proteins on or off. This new study, which primarily examined brain cells grown in the lab, shows that where MAST3 turns ARPP-16 on, PKA can turn it off. The competition between these two proteins turns ARPP-16 into a highly sensitive chemical switch, known as a ‘toggle switch’, that allows cAMP to precisely influence the activity of PP2A. Ultimately, this means that an increase in cAMP will free PP2A from inhibition.
PP2A has many roles inside different cells, the question of how it is possible for one protein to have so many different jobs is complex and involves many other cell components. This study adds to our understanding of PP2A but there are still many unanswered questions about the regulation of ARPP proteins and their effects on PP2A in other cell types.
Dr Le Novère said: “The ARPP proteins were discovered as targets for PKA, we didn’t know what PKA was doing. We’ve now shown that PKA and MAST3 compete to turn ARPP-16 on or off. This means PKA can stop ARPP-16 from inhibiting PP2A. We used mathematical modeling to show that this set of interactions create a switch-like response to cAMP. This creates a mechanism whereby cAMP stops the inhibition of PP2A.”
Musante, V. et al., Reciprocal regulation of ARPP-16 by PKA and MAST-3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition., eLife 2017 Jun 14;6. doi: https://doi.org/10.7554/eLife.24998
A computer model of the molecular structure of the three protein chains that make up PP2A. Based on data published by Cho et al. in Nature 2007 Jan 4;445(7123):53-7.
Image source: Opabinia regalis via wikimedia commons, CC-BY-SA.
Affiliated Authors (in author order):
Lu Li Signalling Programme, Babraham Institute
Nicolas Le Novère, Group Leader, Signalling Programme, Babraham Institute
About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. It's goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.
Animal research statement:
As a publically funded research institute and a signatory of the Concordat on Openness in Animal Research, the Babraham Institute is committed to engagement and transparency in all aspects of its research. This study was primarily performed using established cell lines grown in the lab. Verification work performed using mice was carried out at Yale University.
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18 July, 2017