Cell Signalling and Protein Phosphorylation: A New Type of 'Switch'
October 17, 2016 | Francis Crick InstituteEstimated reading time: 2 minutes
Scientists from the Francis Crick Institute and the Leibniz Institute of Molecular Pharmacology in Berlin have turned the field of protein phosporylation on its head by showing that phosphorylation of multiple protein sites by the same enzyme does not, as previously thought, act in the same direction.
They propose a new mechanism whereby these modifications trigger opposing effects in being able to activate as well as inhibit the function of a protein substrate.
Reversible protein phosphorylation in response to cell signaling is implicated in many human diseases including many cancers. It is the focus of extensive research into ways to treat these diseases.
Phosphorylation is a process where a chemical modification called a phosphate group is added to a protein, activating or deactivating it or otherwise changing its function.
A number of different enzymes are involved in phosphorylation. Enyzmes called kinases add phosphates and enzymes called phosphatases remove them, resetting their function to prestimulation level. Until now it was thought that kinases and phosphatases act together and unidirectionally, relying on each other's antagonistic activities to adjust protein activity.
Anastasia Mylona, a postdoc in Richard Treisman's group at the Crick, led the work. The researchers studied a protein called
Elk-1, that plays an important role in turning the genes on when a cell receives a signal to proliferate. Such signals activate a kinase called ERK which adds phosphate groups at multiple sites on
Elk-1.
Dr Treisman explains: "Our work discovered a phosphorylation switch in which the action of ERK turns Elk-1 activity both on and off. Sites that become modified fast act positively, whereas sites that are phosphorylated more slowly act negatively. The kinase thus first acts positively, but with time it also phosphorylates the slow sites, and limits Elk-1 activity. Importantly, this 'resetting' does not require the action of a phosphatase - that is, the active removal of phosphorylation marks."
With their collaborators in Berlin, led by Philip Selenko, the research team tracked the phosphorylation process of Elk-1 using time-resolved NMR spectroscopy, a technique that enabled them to look at both the sites of phosphorylation and simultaneously measure their rates of modification.
They then used mathematical modeling to understand how these rates depended on and affected each other, leading to the classification of fast, intermediate and slow Elk-1 phosphorylation sites.
Dr Treisman says: "Our results propose a new way in which cells can respond to a signal that is non-linear - that is, not strictly proportional to its strength. This may be particularly important in the Elk-1 system, which controls a gene network that determines cells' sensitivity to growth promoting signals."
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