May 31, 2002 Researchers from the Johns Hopkins School of Medicine have learned that a protein that prevents the formation of cancerous tumors in animals also helps single-celled amoeba determine direction, particularly when moving toward a chemical attractant, an ability of many cell types in more complex creatures. Reporting in the current issue of the journal Cell, the scientists show that a protein called PTEN goes to the back of the cell when a chemical attractant is sensed, allowing the cell to move purposefully toward the attractant. Because PTEN "brings up the rear," the molecules crucial for allowing the cell to reach out and move forward are restricted to the front of the cell.
"How do cells determine which direction to go to find an attractant? How do they sense the differences in concentration of the chemical, alter their membranes and move forward?" asks Peter Devreotes, Ph.D., professor and director of cell biology in the school's Institute for Basic Biomedical Sciences. "It's a very complex puzzle, and we've found another piece."
Postdoctoral fellow Miho Iijima, Ph.D., and Devreotes used specially labeled versions of PTEN that glowed green to see where the protein is in the cell during movement of living amoeba. They also monitored the movement and sensing abilities of amoeba whose PTEN gene was removed or altered.
"PTEN is found only in the back of the cell in moving amoeba, and is actually attached to the cell's membrane," says Devreotes. "Without PTEN or without it attached properly, the amoeba couldn't determine direction as well. Instead of moving in a straight line and adjusting quickly if the source of the attractant is moved, cells without PTEN have bigger 'fronts' that tugged them in a number of directions at once, impeding their progress."
In the same issue of Cell, other researchers report that another protein is found only in the front of amoeba. The two reports fit well together because PTEN and the other protein, called PI 3-kinase, have opposite functions -- the PI 3-kinase puts a phosphate group on a particular molecule, PTEN takes it back off, Devreotes explains.
The studies also show that this molecule, which is part of the cell membrane, is a key player in amoeba's ability to create a "pseudopod," literally a false foot, to move toward the attractant. While they are still investigating exactly how the molecule's active form, which has the additional phosphate, helps the amoeba move, the new results explain why it is found only at the front of the cell.
When the cell isn't moving, its membrane is made up largely of a two-phosphate version of the molecule, abbreviated PIP2, that helps the membrane keeps its shape. As the cell senses an attractant and needs to move, the kinase up front adds a phosphate group to the molecule, which is then called PIP3. PTEN's presence at the sides and rear of the cell ensures that PIP2 stays PIP2 everywhere else.
Interestingly, PTEN isn't just floating near the membrane at the rear of the cell, but is actually bound to it, Devreotes reports. The results show that PTEN has two critical regions: that responsible for binding to the cell's membrane, and the one that removes a phosphate from PIP3, says Devreotes.
"No one has reported seeing PTEN on the cell membrane before, but we show that its binding to the membrane is crucial to help the cell sense direction," says Devreotes. "Having the correct distribution inside the cell is as important as being able to remove the phosphate group."
In many types of cancer the human version of PTEN is mutated, quite often in the protein's binding region. Based on their observations in amoeba, the researchers suspect those mutations may alter the protein's cellular distribution, adversely affecting its ability to halt cell division, its normal function in human and animal cells.
It's not known if PTEN in human cells is also involved in directional sensing or cell mobility, notes Devreotes, even though it is very similar in sequence to the amoeba's version and also removes phosphate groups from PIP3. If it is, the findings could have implications in understanding the spread of cancer from one part of the body to another, a process known as metastasis.
The studies were supported by grants from the National Institutes of Health.
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