JHU Med 2002-49 (anti-cancer protein and cellular motion)

[Dennis O'Shea]

Johns Hopkins Medical Institutions
Office of Communications and Public Affairs
Media Contact: Joanna Downer
410-614-5105
E-mail: jdowner1@jhmi.edu
May 30, 2002

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EMBARGOED FOR RELEASE ON THURSDAY, MAY 30, AT 5 P.M. EDT
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CANCER-SUPPRESSING PROTEIN IS PART OF AMOEBA'S COMPASS

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.

On the Web: http://www.cell.com

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