Utrecht researchers have developed a new method to determine the activity of kinases. This group of enzymes is involved in cellular processes such as cell division and cell death, and is therefore a driving force behind cancer. Researchers from Utrecht University describe their discovery together with colleagues from Sanquin and the NKI 11 september in Cell Systems.
Utrecht researchers develop new technique for measuring protein activity
New method for early detection of cancer
Kinases play a crucial role in cell processes. These enzymes regulate the activity of proteins involved in cell division, cell growth and cell death. Kinase activity can therefore disrupt the process of normal cell division and play a role in the development of cancer. But there was no direct way to detect this kinase activity – and therefore cancer – yet. "Until now, the activity of a kinase could only be predicted by looking at the substrates of the enzyme”, lead author Maarten Altelaar.
Maarten Altelaar's group, together with colleagues, developed a new molecular method to determine kinase activity with great precision. "We do this by measuring protein phosphorylation: a molecular mechanism in which kinases attach a phosphate group to another protein, turning it to an active state", says first author Thierry Schmidlin. "In that sense, protein phosphorylation is similar to a light switch, and kinases are the enzymes orchestrating which proteins to turn on at which times.” Kinases themselves are in turn activated in a similar way by phosphorylation.
Using samples from a breast cancer patient, they now show in Cell Systems that this method is more sensitive than current methods. “The amount of material in patient samples is very limited if it originates from a needle biopsy. Therefore the sensitivity of an analytical method is paramount”, says Thierry. “By detecting which kinases are active, they can also be tackled in a more targeted way. Especially detecting activation of various kinases that can be inhibited by approved drugs or drugs currently involved in clinical studies is promising.”
The method is so successful that Altelaar has already applied for a patent on the technology. At the moment, they are also applying the technology to a recent discovery that they published together with NKI colleagues in Cell on 11 July. In this paper they describe how inactivating specific genes can help to make tumor cells more sensitive to immunotherapy. Altelaar: "This also looks very promising."
High-throughput assessment of kinome-wide activation states. Thierry Schmidlin*, Donna O. Debets*, Charlotte A.G.H. van Gelder*, Kelly E. Stecker*, Stamatia Rontogianni*, Bart L. van den Eshof, Kristel Kemper, Esther H. Lips, Maartje van den Biggelaar, Daniel S. Peeper, Albert J.R. Heck* and Maarten Altelaar*. Cell Systems, 11 september 2019 DOI: 10.1016/j.cels.2019.08.005
Augmenting immunotherapy impact by lowering the tumor TNF cytotoxicity threshold. David W. Vredevoogd,Thomas Kuilman, Maarten A. Ligtenberg, Julia Boshuizen, Kelly E. Stecker*, Beaunelle de Bruijn, Oscar Krijgsman, Xinyao Huang, Juliana C.N. Kenski, Ruben Lacroix, Riccardo Mezzadra, Raquel Gomez-Eerland, Mete Yildiz, Ilknur Dagidir, Georgi Apriamashvili, Nordin Zandhuis, Vincent van der Noort, Nils L. Visser, Christian U. Blank, Maarten Altelaar*, Ton N. Schumacher, and Daniel S. Peeper. Cell, 11 juli 2019, DOI: 10.1016/j.cell.2019.06.014
* authors affiliated with Utrecht University