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09Jun 2017

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New method uncovers complex cellular signal routes

Thijn Brummelkamp research lab

Researchers of the Netherlands Cancer Institute developed a method for studying communication routes in the cell. With a combination of DNA sequencing and antibodies they can now map the genetic regulators of virtually any human protein. By comparing these regulators under different conditions they can now study how the regulators work together. For example, they identified the mechanism of a new inhibitor of the GPCR receptor family, members of which are often deregulated in cancer cells. Group leader Thijn Brummelkamp and several of his team members published their findings in Nature on May 31st.

Many experimental approaches are designed to study how biological processes are regulated in human cells. Markus Brockmann and his colleagues have now developed an approach which makes it possible to identify and compare regulators of virtually every protein in the human cell. Co-author Vincent Blomen: "With our combination of antibodies and DNA sequencing we can now get an overview of complex signaling pathways in the cell."

With their new setup the research team studied the genetic regulation of various cellular processes, such as epigenetic modifications, signal transduction pathways and organelle regulation. Starting with a technique called gene-trap mutagenesis they induce random mutations in single genes of human haploid cells, thereby switching these genes off. After staining with antibodies they then select cells based on their phenotype, such as containing either a high or a low amount of a certain protein in a certain state or form. By sequencing the DNA of the mutated cells with high or low levels they can discover new links between genes and phenotypes.

Now, finding a genetic regulator is one thing. Understanding the underlying regulatory mechanism is a whole different - and even more difficult - matter. This is the part where this new approach stands out, says co-author Vincent Blomen: "It is known that most genes act in complex systems with other genes and it has been difficult to predict these genetic interactions. With our sensitive approach we can now uncover these interactions by changing the genetic background of cells and study how their genetic wiring changes."

While studying these genetic interactions, Brummelkamp's team discovered a new inhibitor of the important GPCR receptor family. First, they found the protein KCTD5 to be a previously unknown regulator of AKT (protein kinase B), which is part of a key signaling pathway frequently deregulated in cancer cells. By subsequently studying different knock-out cells they discovered that KCTD5 influences AKT by negatively regulating the beta-gamma subunits of GPCR receptors. Blomen: "GPCR signaling has been studied for a long time and there are known inhibition systems for several common parts of this receptor family, but not the beta-gamma subunit. We now identified a mechanism that switches of this beta-gamma subunit and thereby dampens GPCR signaling."

The technology published in Nature is part of the technology platform of Scenic Biotech, a spinout therapeutics company of the NKI and Oxford University. Thijn Brummelkamp is co-founder of the company, which recently raised 6,5 million euros for advancing their technology.

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