(left to right) Estela Jacinto, PhD, assistant professor, Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School; Nelyn Soto, MS, research assistant; Carolyn Lowry, BS, research assistant

They live and die. They crawl, scavenge and expand. In times of plenty, they grow and proliferate, and in times of dire need, they can even chew themselves up. Indeed, the cells of our body are just like us, constantly responding to the surrounding environment. The series of events that are triggered by an environmental stimulus such as food, it turns out, are as complicated for an individual cell as for the whole being. We are interested in deciphering the messages that are passed on from outside to the inside of a cell and how a response is ultimately decided. When food is the message, who are the messengers and what are the consequences? We focus on a protein called TOR, whose discovery can be traced back to the island of Rapa nui, as an important messenger of food availability among cells.

email this print this Share this: digg this! del.icio.us facebook newsvine

A cell employs a whole army of multi-tasking professionals to pass on messages signaled by the environment. The chemical composition of these professionals could be quite diverse. It could be as simple as an ion (calcium for example), or as complicated as lipids and proteins. And like any efficient professional, they don’t just sit around, they are very interactive, mobile, and are highly specialized yet flexible. Unfortunately, as professional as they can be, they are also subject to errors, either in-born or acquired. When unchecked, these errors could cause a major screw-up that could shut down the whole establishment and cause neighboring establishments to follow suit. This is how a disease transpires. Therefore, deciphering how messages are propagated by professionals is the key to understanding how diseases can occur and how they can be stopped.

Among these professional messengers, we are interested in a class called protein kinases. A kinase is an enzyme and functions to catalyze chemical reactions. When a message is received from the outside, a kinase becomes activated or energized and can in turn activate another kinase or another protein. Activation comes in the form of phosphates; hence, this reaction is also termed phosphorylation. There are over 300 protein kinases encoded by the human genome. We focus our studies on a kinase called TOR, which stands for the target of rapamycin.

Rapamycin was first discovered in the soil samples from Rapa nui, also known as Easter Island, home to the legendary stone statues or moai. Rapamycin has potent anti-mitotic properties and is currently used in the clinic as an immunosuppressant, and to prevent restenosis of coronary stents after angioplasty. It is undergoing clinical trials as an anti-cancer drug. Early studies in yeast have shown that rapamycin inhibits TOR.

TOR is also found in higher organisms such as plants, worms, flies, and mammals. Thus, it is reasonable to say that TOR performs very basic cellular functions or must pass on a very important message that even simple organisms like yeast receive. Indeed, this important message says “There is food, now grow!” TOR receives or senses the presence of food (nutrients) by mechanisms we don’t know yet. But we do know that by passing on the message to other proteins, the cells grow and divide and live normally. We know all this because when we inhibit TOR by using rapamycin, or by genetic manipulations that weaken TOR, cells think they are starving even when food is around! Starvation, of course, when prolonged, leads to death. When there’s too much food, can cells overeat, too? Can we make TOR overactive so cells think the sky’s the limit? A number of messengers in the mTOR route, but not mTOR itself, have been found to be over-activated, making cells think food is aplenty; hence they multiply uncontrollably and become cancer cells.

In mammals, TOR also responds to the messages sent by other cells from another organ in the body. The messenger here is a hormone like insulin, which is produced by pancreatic cells, and the message also spells food. Thus, in mammals, mammalian TOR (mTOR) passes on signals coming from both insulin and the surrounding nutrients, triggering a whole network of signaling events whose end result is the growth and proliferation of cells. But what happens when environmental conditions are not so optimal? What happens when the organism is exposed to challenging situations? Surely, availability of food is not the sole preoccupation of cells either.

The cells of the body have also evolved mechanisms to deal with stressful conditions and a number of professionals have been identified that function in stress-management to enable cells to survive. Recently, our lab discovered that mTOR can perform such a task as well that is not inhibited by rapamycin. How is this possible? We found that mTOR forms two separate gangs or “protein complexes.” One of these complexes does not bind rapamycin. This complex can pass the message coming from insulin to another protein kinase called Akt that is known to be mutated in a number of cancer cells. These findings suggest to us that mTOR could pass on another important message that allows cells to survive. Cancer cells are characterized by uncontrolled growth and proliferation despite adverse conditions; hence it is thought that they have “hijacked” the survival professionals to make them work for their cause. It is therefore important to understand how we can intercept the message that allows these cells to survive. By inhibiting the function of mTOR in survival, we may be able to promote death of these abnormal cells.

As a messenger of food availability, mTOR could therefore play a role in a number of diseases. Surprisingly, there has been no mTOR genetic mutation in humans reported so far. mTOR must be a very essential gene — its mutation is lethal from yeast to mice, and most likely in humans as well. Interestingly, there are a number of proteins that are linked to mTOR that can be mutated, leading to pathological conditions. Akt, as mentioned above, is a prime example. There is also TSC (tuberous sclerosis complex), which serves as a control hub for messages received from insulin. When this hub gets out of control, cells get abnormally big. Mutations in TSC cause a disorder called tuberous sclerosis, a disease characterized by benign tumors of particular organs in the body. Hence, the mTOR inhibitor, rapamycin, is

Figure 1

Figure 1. How do extracellular signals determine cell fate? For unicellular organisms like yeast, the availability of nutrients signals the cell to grow and proliferate. For multicellular organisms like humans, nutrients, together with other stimuli such as hormones, dictate growth, proliferation, survival, or differentiation. The target of rapamycin, TOR (TOR in yeast, mTOR for humans) mediates signals coming from these stimuli. Environmental stresses impact these signals and can inhibit TOR, leading to inhibition of cell growth.

Figure 2

Figure 2. mTOR responds to nutrients and insulin to control growth, proliferation, and survival. mTOR forms two distinct protein complexes to perform distinct functions. mTOR, in association with raptor and mLST8, promotes growth or increase in cell size. This function of mTOR is inhibited by rapamycin. mTOR, in association with rictor, SIN1 and mLST8, promotes Akt activation, leading to cell proliferation. Under stress conditions, the activation of Akt by mTOR promotes cell survival.

being tapped as a treatment for this disease. mTOR could also serve as an important target for metabolic-related diseases such as diabetes and obesity. Indeed, in mice, it has been shown that genetic deletion of one of the messengers of the mTOR route, S6K1, generated lean mice that can eat a high-fat diet without getting fat. Finally, from yeast to flies, research has already shown that mutation of the mTOR route increases life span of these organisms. Could mTOR hold the message of Methuselah? We can only hope to live long enough to understand the contents of this message.

Estela Jacinto is an assistant professor in the Department of Physiology and Biophysics at UMDNJ-Robert Wood Johnson Medical School. She received her BS in zoology from the University of the Philippines in 1986 and her PhD in biomedical sciences in 1997 from the University of California, San Diego, where she studied signaling in T lymphocytes in Michael Karin’s laboratory. Her interest in immunosuppressants led her to the laboratory of Michael N. Hall, where she started her research on TOR in both yeast and mammals as a post-doctoral fellow at the Biozentrum, University of Basel, Switzerland.