Like the old-time telephone networks run by switchboard operators, our cells have their very own "switchboard operators" that allow external signals to place a "call" to various cell centers such as the nucleus and other cellular organelles.
These "switchboard operators" are receptors – proteins that sit on the outer membrane of the cell wall. When they receive "incoming calls" – in the form of chemical molecules, such as insulin, or physical stimuli, such as heat – they become activated, transferring the message to the nucleus inside the cell. The cell then responds to these external stimuli, initiating cellular functions according to the specific message received. These functions include proliferation, differentiation, survival and even cell death.
t was as a postdoctoral fellow working in the laboratory of Nobel laureate Edwin Krebs that Prof. Rony Seger of the Weizmann Institute's Biological Regulation Department first encountered these messages being passed on once the receptor was activated. Signaling pathways – the cells' version of telephone lines – comprise about five to eight proteins each. These proteins, like runners in a relay race, activate the next protein in line until the last one crosses the finish line – in this case, the nuclear membrane.
Rather than electrical signals, as in telephones, the proteins use chemical signals, adding a phosphorus molecule to each "runner" in turn.
Through the Human Genome Project, it was discovered that cells employ only 100-200 "operators" at a time to receive hundreds of incoming calls. Each call requires an individual response, but just 10-12 main "telephone lines" are available to transfer messages. "How are all these different signals transmitted and responded to with such specificity?" wondered Seger.
Over the years, Seger has managed to identify various ways in which specificity is achieved; the most recent findings were published in the Journal of Cell Biology. Together with postdoctoral fellow Dr. Yoav Shaul, he has now shown that the main signaling pathways can branch out and subdivide – something like extension numbers in automated answering systems that prompt "Please press 1 for…, 2 for..."
This discovery came about when they were studying one of the main signaling pathways, called ERK, and noticed that it had various "extension numbers" – namely, ERK1, ERK1b, ERK1c and ERK1d. "The question was whether these extensions are redundant, dealing with the same 'queries' as the main ERK pathway, or whether they handle different messages of their own," explains Seger.
It turns out that the extensions do indeed have very specific functions. One role of the ERK signaling pathway is the regulation of cell division. During cell division, one of the cell's components – the Golgi apparatus – splits into thousands of tiny fragments that are doled out among the daughter cells for later reassembly. Seger found that only one of the ERK branch lines, ERK1c, was capable of transmitting the message to carry out this process.
Because breakdown in communication can lead to malfunction in cellular processes, discovering how specific messages are delivered may prove to be of major importance. For example, ERK signaling inhibitors are currently used to try to modulate the excessive cell growth of cancer, but because ERK is a main pathway involved in many cellular functions, jamming the signal may interfere with some necessary ones as well. The ability to target a specific pathway could lead to a more effective treatment and cause fewer side effects in the process.
Prof. Rony Seger's research is supported by the M.D. Moross Institute for Cancer Research; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and La Fondation Raphael et Regina Levy. Prof. Seger is the incumbent of the Yale S. Lewine and Ella Miller Lewine Professorial Chair for Cancer Research.
Cell to Cell
A surprising discovery in the lab of Prof. Rony Seger has shown that the body's cells appear to be able to "answer" calls made by cell phones. Our cells apparently pick up the radiation signals transmitted from cell phones and respond to the messages they are receiving.
Seger and Dr. Joseph Friedman, working part-time in Seger's lab, exposed living cells grown in lab dishes to cell phone radiation emissions in the range of frequencies and intensities used by cell phone networks for up to 45 minutes – well within the range of the average teenage phone conversation.
The researchers found that the "calls" placed by cell phone radiation were transmitted to the human cells via the ERK line – one of the more prominent intracellular telephone lines described here. Once the ERK line was activated, the cells were able to respond, providing various "answers" – adjusting cellular activity depending on the radiation frequency and intensity they were exposed to.
Do these findings suggest that cell phones "connect" to the central ERK line directly? Seger and Friedman suspect that cell phone radiation emissions first "call up" another set of molecules, known as free radicals. Free radicals are highly reactive molecules that are created in cells and may, under specific conditions, participate in the regulation of normal cellular processes such as proliferation, or pathological processes such as cancer. These, in turn, might activate the ERK telephone line.
The implications for human health are unknown at this point. To investigate further, Seger and Friedman intend to move their research up a step, from living cells to living organisms. This may lead to a better understanding of the effects of cellular phone radiation on living cells and help in assessing its effects on the human body.