Ras protein choreographs cell life

By Ruth SoRelle, M.P.H.

Many students come away from high school and undergraduate biology classes with the impression that the cell is a bag of fluid in which proteins swim and somehow collide, sparking a chain of chemical reactions.

Increasingly, however, it has become apparent that cells have a complex geography with many compartments and that proteins can dynamically move between these compartments.

Why does this matter?

In a recent study, Eric Chang, Ph.D., assistant professor in the Baylor College of Medicine Breast Center and department of Molecular and Cellular Biology, and colleagues demonstrated that the activity of a key player for cancer formation called Ras differs depending on its location.

"Our studies unambiguously demonstrate this," said Chang. His work appears in a recent issue of the Proceedings of National Academy of Science. "Ras does one thing in one part of the cell and in another part of the cell it does something else."

The ras gene, which encodes the Ras protein, was one of the first tumor oncogenes or cancer-causing genes discovered.

"In the early 1980s, very little was known about what caused cancer," said Chang. "However, scientists noted that some retroviruses induced phenotypes (outward signs and symptoms) that were tumor-like in tissue culture cells, and ras was one of the genes carried by a strain of retroviruses."

However, when scientists later analyzed the DNA from human tumors, they discovered mutations in ras genes that were identical to those found in the retroviruses.

Commonly mutated genes

"Ras is one of the most commonly mutated genes in human tumors," said Chang. "For example, ras mutations can be found in 30 percent of human tumors, and in some tumors, such as those of the pancreas, as many as 90 percent of them can carry ras mutations."

Understanding how Ras induces cancer is complicated by the fact that there are four Ras proteins with a highly similar protein structure that can regulate different activities.

For example, only mutations in the K-ras gene are widely found among human tumors, while mutations in N-ras are most frequently found in lymphoma.

Some early studies have shown that some Ras proteins reside in cell compartments that are different from other Ras proteins, thus raising the possibility that a given Ras protein may control a unique function by moving and staying in a particular cell compartment. However, it is very difficult to test this idea in human cells because they commonly express all four Ras proteins.

Targeting the pathway

In his study, Chang and his colleagues focused on an organism called Schizosacchromyces pombe or fission yeast because it has only one Ras protein that controls two different pathways. Without the use of any sophisticated tools, one can easily know which Ras pathway is operative. For example, one Ras pathway controls how signals from the outside trigger the cell to mate while the other controls internal as yet unidentified signals that influence cell shape. Mating and cell shape can easily be seen through a microscope.

The Chang team altered the Ras1 protein so that its action was restricted to either the endomembrane in the interior of the cell or the plasma membrane that forms the most outer barrier separating the cell from its environment.

Remarkably, the Ras1 protein targeted to the endomembrane supports the "cell shape" pathway, while the plasma membrane-restricted Ras1 activates only the mating pathway.

In human cells, the Ras pathway that is similar to the yeast mating pathway controls the signals that affect growth factors. The human Ras pathway that is similar to the pathway that controls the shape of the yeast cell regulates cell movement. It is conceivable that deregulation of these pathways (which would occur when the Ras proteins are mutated or deleted) can promote uncontrolled cell proliferation and metastasis, leading to the formation of malignant tumors.

Predicting risks, targeting therapy

"So far most of the ras mutations reported in the literatures lock the Ras protein in a permanently activated state. However since we do not know where these mutated Ras proteins function in the cell, it may be difficult to predict what impact this mutation has on tumor formation," said Chang.

Better understanding of where proteins function in the cell can better aid physicians in predicting cancer risks and in targeting therapy to short-circuit the formation of tumors.

"Ras is frequently at the crossroads of deciding the fate of the cell," said Chang. The protein is often involved in deciding whether the cell should replicate, remain dormant, differentiate into a different cell type, or follow the dictates of programmed cell death—a process called apoptosis. As such it is not surprising that tumorigenesis (or tumor formation) chooses Ras as a convenient switch to reprogram the cell."

This work was funded by the National Institutes of the Health, the U.S. Department of Defense, The Susan Komen Foundation and the Burroughs-Wellcome Fund.

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