KRas moves between various membranes within the cell, so that it is available in a sufficient quantity at its actual destination
The cancer protein KRas is a factor in the development of several types of cancer. Mutated KRas, for example, can be found in a large number of all tumour cells in patients with pancreatic cancer. It sits on the inner leaflet of the cell membrane and relays signals into the cell’s interior.
Distribution of the cancer protein KRas in a cell.
© M. Schmick
Scientists at the Max Planck Institute of Molecular Physiology in Dortmund have now discovered why KRas is almost exclusively found at the cell membrane when observed under the microscope. Apparently, the protein is not specifically sent to the cell membrane after it is formed, but is also located on other membrane systems within the cell for its entire life span.
In order for it to be transported by special transport vesicles from the vicinity of the cell nucleus to the cell membrane, the solubilising factor PDEδ and its antagonist Arl2 must be active. Without the two of them, KRas would spread to cell membranes. The researchers can use their results to better understand how deltarasin works, which is a potential anti-cancer drug that they have developed.
The protein KRas acts as a molecular switch in relaying signals to the cell’s interior. Among other things, such signals control cell growth. In order for KRas to be able to function correctly, it must remain on the inner leaflet of the cell membrane for a sufficient period of time. Its water-insoluble lipid anchor helps it to achieve this.
However, this also anchors the protein to other intracellular membranes. KRas therefore has an area of positive charges near this lipid anchor. Similar to a polystyrene ball in a plastic bag, the electrostatic interaction of these positive charges with the negatively charged inner leaflet of the cell membrane reinforces the lipid anchoring.
But even lipid anchor and positive charges are not enough to ensure that KRas is permanently enriched at the cell membrane. According to the results obtained by the researchers in Dortmund, many KRas molecules would still be lost on the available surface of the rest of the membrane systems in the cell, which is 200 times bigger than that of the cell membrane. Using complex computer simulations, the scientists evaluated data from fluorescence microscopy experiments and tracked the movement of KRas on its journey though the cell.
“Our results show that the cell membrane is by no means the final destination of KRas, which must only be encountered once. Instead, KRas constantly and unspecifically re-distributes to the various membrane systems of the cell and must then be concentrated on the inner leaflet of the cell membrane via a continuous cycle,” explains Malte Schmick from the Max Planck Institute of Molecular Physiology.
In the first step of this cycle, the soluble protein PDEδ shields the lipid anchor of KRas like a glove, thus making KRas water-soluble. This prevents KRas from simply finding some arbitrary membrane. Swimming in the cytoplasm, KRas can thus explore the cell. When it gets close to the nucleus of the cell, the activity of the protein Arl2 removes this glove. KRas is now insoluble in water again and can be trapped on membranes and transported back to the cell membrane by vesicles.
The cell therefore does not have a unique targeting system for KRas, which sends it exclusively to the cell membrane. Instead, the protein redistributes to all membranes and is repeatedly sorted from the wrong membranes to the correct one. “Each KRas molecule lives for several hours before the cell disassembles it again. After seven minutes, half of all KRas molecules are internalized from the cell membrane to be subjected to the cycle and sent back to the cell membrane. In total, each KRas molecule travels for approximately 20 minutes before it reaches the cell membrane again,” says Schmick.
The results obtained by the scientists in Dortmund pave the way for the development of new cancer drugs. This is due to the fact that KRas is modified in many forms of cancer to such an extent that it is permanently active and the cell can no longer switch it off. One-third of all tumours contain cells with mutations of Ras proteins. In the case of intestinal cancer for example, mutated KRas prevents successfully using antibody treatment against epidermal growth factor receptors (EGFR).
“We can now develop active agents that reduce the enrichment of mutated, permanently active KRas at the cell membrane,” explains Philippe Bastiaens, Director at the Max Planck Institute in Dortmund. In 2013, he worked with colleagues Herbert Waldmann and Alfred Wittinghofer to develop an inhibitor, known as deltarasin, to block the PDEδ solubilizing activity. Initial experiments on mice have shown that the active agent considerably slows the growth of tumours. Even though scientists had been aware of the relevance of PDEδ for a while, this work now explains for the first time the mechanism by which deltarasin prohibits KRas from being enriched at the cell membrane and causes it to be distributed throughout the entire cell.
Prof. Dr. Philippe Bastiaens | Max-Planck-Institut
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
Snap, Digest, Respire
20.01.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Life Sciences
20.01.2017 | Physics and Astronomy
20.01.2017 | Materials Sciences