Another tool in the war against cancer - disrupting its transmission

Excessive transmission of the signals commanding cells to divide may cause the development of cancerous tumors.

Poor communication can have disastrous results. This is true not only for interpersonal relationships, but also for biological processes. Thus, for example, excessive transmission of signals that command cells to divide may cause the development of cancerous tumors. A team of scientists from the Weizmann Institute of Science recently identified a protein that blocks the excessive transmission of such signals. The research findings may lead, in the future, to the development of improved treatments for certain types of cancer. Prof. Yosef Jordan from the Department of Biological Control at the institute is investigating one of the biological "lines of communication": an array that includes a receptor found on the outer side of the cell membrane, and a growth factor called EGF. Binding of EGF to the receptor causes the transmission of messages into the cell, instructing it to divide. In order for the message to be transmitted, the receiver must enter the "on" state. Activation of the receptor is done through a chemical change: it attaches several atoms of phosphorus to it. The receptor is in an "activated" state for only a short time: the phosphorus atoms are torn off, and the receptor itself is "sucked" into the cell and transferred - inside a small vesicle - to special organelles called endosomes, where it undergoes decomposition. In some cases of cancer, such as breast cancer and colon cancer, there is overactivity of EGF receptors. Is it possible that this increased activity is caused by defects in the "stopping" mechanism of the receptor, that is, in the removal of the phosphorus molecule?

To test this hypothesis, the team of scientists - which included research student Gabi Tersik, as well as Dr. Shlomit Bogolovski, research student Jean Wakim and researchers from King's College London, from the University of California in Los Angeles, and from Vanderbilt University in Tennessee - scanned 40 "suspicious" proteins ". All these proteins, called phosphatases, are responsible for removing phosphorus molecules from other proteins. The researchers blocked, one by one, the activity of the phosphatases, with the aim of checking which of them performs the chemical change in the EGF receptor. The scan showed that two of the 40 phosphatases affect the receptor. The involvement of one of the two is already known and known, but the other - called DEP1 - is a new player in the field. Scientists did discover, in the past, that this is a cancer-suppressing protein, which blocks cancerous processes. However, there was no information about its mode of action, and its involvement in the mechanism of action of the EGF. The scientists sought to understand exactly how DEP1 affects the EGF receptor. In the first step, they proved that the receptor and the phosphatase do bind to each other, and that blocking DEP1 encourages cell proliferation - and therefore may cause the development of cancerous tumors. In the next step, the scientists approached to reveal the details of DEP1's activity.

It turns out that DEP1 has a very important effect. The phosphatase is located on the outer side of the cell membrane, and detaches the phosphorus atoms from the receptors immediately before they are pumped into the vesicles that lead them into the cell. In fact, this action slows down the movement of the receptors on their way to the endosome. Blocking the phosphatase activity causes the phosphorus atoms to remain on the receptors. In this case, small "labels" called ubiquitin are attached to the receptors. These labels speed up the travel of the receptors to the degradation site. However, with this new composition of proteins, the EGF receptors not only continue to transmit their signals into the cell, but do so with greater intensity. When DEP1 works normally, and detaches the phosphor atoms, no ubiquitin labels are attached to the receptors. In this case, the receptors travel more slowly, and their signal is too weak to cause the cell culture to continue. Today, there are already several anti-cancer drugs based on the activity of the EGF receptor. The current study sheds light on the activity of a natural cancer suppressor, DEP1, which works to regulate the transmission of the EGF receptor, and it is possible that it plays additional roles in controlling activities related to the development of cancerous tumors. These findings may help, in the future, in the development of effective drugs for some types of cancer.