Cell Communication Discovery Opens up new Possibilities for Cancer Research
24 February 2017 – New findings on how communication is coordinated between the inside and outside of a cell is set to open up new avenues for further research into treatments for cancer, Alzheimer’s and diabetes.
PERK, an enzyme known to detect protein folding errors in the cell has now also been revealed to coordinate the communication between the inside and the outside of the cell. The discovery was made by researchers at the Laboratory of Cell Death Research & Therapy at KU Leuven in Belgium on a project funded through H2020 Project TrainERS, which is coordinated by Prof Afshin Samali, CÚRAM Researcher and Professor of Biochemistry and Director Apoptosis Research Centre (ARC) at NUI Galway.
Proteins such as insulin are properly formed in the endoplasmic reticulum (ER), one of the biggest membrane structures in the cell. The ER works like an assembly line and folds the proteins into a three-dimensional shape that is essential for them to function. When there is a problem in the ‘protein folding assembly line’, the accumulation of misfolded proteins can lead to diseases such as Alzheimer’s, cancer, and diabetes.
An essential component of this protein folding factory is PERK. “This protein is known to play a crucial role in maintaining ER functions and restoring them if necessary,” explains Patrizia Agostinis, head of the KU Leuven Laboratory of Cell Death Research & Therapy. “When PERK detects protein folding errors in the ER it prompts the nucleus of the cell to take action.”
Patrizia Agostinis, Alex van Vliet, and other team members at KU Leuven discovered an additional function of PERK. Agostinis “We found that PERK also coordinates the communication between the protein folding factory (the ER) and the skin of the cell (the plasma membrane). When the protein folding factory detects low calcium levels, the plasma membrane needs to let calcium flow back in. After all, calcium is crucial for the proper functioning of the protein folding factory – the ER, where the calcium is stored – and for the overall health of the cell. And this is where PERK comes in: the protein establishes contact between the two cell components so that they can work together to restore the calcium level.”
“This entire process, which is regulated by PERK, takes place in a matter of minutes or even seconds,” Alex van Vliet adds. “That’s one of the reasons why it went unnoticed until now. We used a new method to reveal the underlying mechanism, and were surprised to find that PERK can control the movement of the ER towards the plasma membrane by modifying the skeleton of the cell.”
“This is an extremely exciting step forward for any researcher involved in understanding the ER stress response mechanistically and quantitatively” said Prof Afshin Samali, “I would like to congratulate the researchers involved and look forward to more exciting developments to come out of the TrainERS programme”.
This project is funded by Research Foundation Flanders (FWO) and by TrainERS, an innovation training network funded by Horizon 2020 and coordinated by CÚRAM at NUI Galway. Alex van Vliet received funding from the Flemish government agency for Innovation by Science and Technology (IWT).
The TrainERS consortium is coordinated by NUI Galway with partners University of Bordeaux, Goethe-University Frankfurt, University of Leuven, Royal College of Surgeons in Ireland, Medical University of Vienna, Imperial College London, Bellvitge Biomedical Research Institute, University of Gothenburg, Randox Teoranta.
Endoplasmic reticulum (ER) stress is emerging as a common feature in the pathology of numerous diseases including cancer, neurodegenerative disorders, metabolic syndromes and inflammatory diseases. Thus ER stress represents a potential therapeutic intervention point to be exploited to develop novel therapies, diagnostic tools and markers for these diseases. However, exploitation is hampered by the shortage of scientists with interdisciplinary training that can navigate with ease between the academic, industrial and clinical sectors, and that have the scientific and complementary skills, together with an innovative outlook, to convert research findings into commercial and clinical applications. This project brings young researchers together with world-leading academics, clinicians and industry personnel, who are united in 1) their goal of forming a network of excellence aimed at understanding the ER stress response mechanistically and quantitatively and 2) applying this understanding to identify and validate the most suitable intervention points in order to provide innovative knowledge-driven strategies for the treatment of ER stress-associated diseases.