Studying how cells respond to stress can reveal the causes of Alzheimer’s and cancer

Disease and treatment 23. jan 2022 3 min Postdoctoral Fellow Ana Martínez del Val Written by Kristian Sjøgren

Researchers have developed a new method that enables them to determine that cells respond to various stressors by moving many of their signalling proteins from one location in a cell to another. This insight may improve understanding of the underlying mechanisms behind how Alzheimer’s disease and cancer develop.

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Every cell in the human body contains signalling proteins that help to determine the cell’s function by getting the cells to carry out specific functions.

Cells very tightly control the function and location of signalling proteins because of their essential role in ensuring the healthy functioning of cells.

So far, researchers have had to spend days studying where signalling proteins are located in cells, but this experimental protocol has now been reduced to 5 hours.

The new experimental protocol enables researchers to determine where the signalling proteins are in the cell much more easily but also how they move around the cell in response to various stimuli.

“The new method enables us to study the dynamics of the signalling proteins and determine how they react to external stimuli within minutes by moving elsewhere in the cell. This provides new opportunities to study cellular functionality, and this can be applied in a wide range of sciences, including biology and biosynthesis,” explains a researcher behind the study, Ana Martínez del Val, Postdoctoral Fellow, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The research has been published in Nature Communications.

Proteins change locations in the cells

Signalling proteins do not just float arbitrarily inside the cell. They may be located in the cytosol, the fluid inside the cell. They may also be in the plasma membrane itself or inside the cell nucleus.

Signalling proteins are located in different places in the cell at different times and have different effects. When the function of the cell needs to change or as a response to the environment, the proteins might move from the plasma membrane to the cell nucleus or vice versa.

In the new study, the researchers discovered how to track the location of not just one protein at a time but all of them simultaneously.

“We used mass spectrometry, which enables us to measure all the proteins in a system at the same time. We have developed this technique to enable us to discover where the proteins are located in the cells. Other researchers have done this before, but their experimental protocols were very cumbersome and time consuming,” says Ana Martínez del Val.

Improving understanding of cellular signalling in cancer cells

In the new protocol, the researchers divided the cell into six distinct subcellular fractions and analysed them separately.

Because the protocol is so rapid and sensitive, researchers can apply it to multiple replicates and points in time, thereby enabling them to determine not only how the signalling proteins move inside the cell but also how they are chemically altered.

The signaling molecules can be phosphorylated by adding a phosphate molecule or dephosphorylated by removing the phosphate molecule again. Phosphorylation generally signals proteins to become active or inactive or to move.

“The protocol is the novel aspect of this study. We demonstrated that we can analyse hundreds of samples in a short time and thus obtain unique insight into the cells’ internal protein signalling. This knowledge is relevant for understanding the differences between healthy cells and cancer cells. The different signalling of cancer cells is vital for the spread of disease, and this can be better studied using this protocol,” explains Ana Martínez del Val.

Insight into proteins relevant to cancer and Alzheimer’s disease

The researchers carried out two experiments demonstrating that they can use their protocol to obtain new knowledge about the dynamics of signalling proteins and their location in the cell at specific times.

The researchers studied what happens in cells when specific receptor proteins on the cell surface are stimulated.

These epithelial growth factor receptors play an important role in developing Alzheimer’s disease and cancer. If the receptors are stimulated too little, a person may develop Alzheimer’s; too much, and the person may develop cancer.

The researchers found that when the receptors are stimulated with epithelial growth factor, the receptor proteins are removed from the cell surface by entering into small intracellular vesicles that transport them to different places in the cell where they can pass on information.

This change occurs within 2 minutes of stimulation and peaks after 8 minutes.

In the second experiment, the researchers examined how the cell proteins respond to osmotic stress: for example, when the concentration of molecules differs inside versus outside the cell.

In this experiment, the researchers found that the ribosomes that translate genetic information into proteins move from the cytosol to the cell nucleus.

This had never been seen before.

“The ribosomes moving may be a defence mechanism to protect them. The protocol does not just save time but also opens up completely new uses and insights that we have not had the opportunity to obtain using the previous methods to study the movements of proteins in cells,” concludes Ana Martínez del Val.

Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution” has been published in Nature Communications. Several of the authors are employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The group has a long-standing interest in applying their proteomics technology developments to systems-wide analyses of dynamic post-translational mod...

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