Abstract
At the end of mitosis, the stiff actomyosin cortex at a cell's poles has to soften so that the cell can elongate and divide. The enzyme PP1, which sits on the kinetochores during metaphase and anaphase, spurs the polar cortex to relax. Polar relaxation is particularly important for cancer cells, and inhibiting it might rein in their division.
A kinetochore enzyme enables cells to elongate as they leave mitosis, thus helping them divide, researchers have found. This elongation might allow cancer cells to create space for themselves within a tumor.
When a cell enters mitosis, an actomyosin cortex forms just beneath the plasma membrane and shapes the cell into a sphere. As the cell leaves mitosis, the spindle stimulates the cortex around the cell's midsection to form an actomyosin ring. Before this ring can contract to separate the cell into two, however, the stiff cortex at the cell's poles has to relax. Researchers haven't understood what induces this change.
A team led by Buzz Baum, PhD, of University College London in the United Kingdom, found that polar relaxation precedes the appearance of the cleavage furrow in Drosophila and human cells. Moreover, when the researchers disrupted furrow formation, the cell cortex still slackened, indicating that the two processes are independent.
Previous studies proposed that centrosomes or astral microtubules stimulate polar relaxation, but Baum and colleagues showed that these mechanisms weren't responsible in the cells they studied. Rather, they found that the trigger, the phosphatase PP1, resides on the chromosomes, which approach the cell cortex as mitosis proceeds.
The team demonstrated PP1′s importance by using light to steer Sds22, the PP1 subunit that activates the enzyme, to the plasma membrane in cells that had stalled in mitosis. The cells showed signs that the cortex was loosening in response to Sds22 at the plasma membrane.
PP1 stimulates polar relaxation by removing phosphates from proteins that help fasten the cortex to the plasma membrane—namely activated ezrin, moesin, and radixin—permitting the cell to stretch out and ultimately divide. Previous studies found PP1-containing complexes in several locations in mitotic cells, including the chromosome arms, but the researchers reported last month in Nature that PP1 concentrates on the kinetochores during metaphase and anaphase.
Baum says that the mechanism he and his colleagues discovered “tells the cell that the chromosomes are coming close to the membrane” and helps coordinate chromosome separation and cytokinesis.
“The mechanism is really elegant … as the chromosomes are segregating they contribute to controlling the cell-shape change,” says Iain Cheeseman, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, MA, who wasn't connected to the research.
“They have a nice handle on a molecular mechanism that induces weakening of the polar cortex,” says Michael Glotzer, PhD, of the University of Chicago in Illinois. The mechanism, he says, “doesn't account for the majority of the shape changes that drive cytokinesis, but it is a contributing factor.”
Polar relaxation is crucial for cancer cells, Baum says. By forming a sphere when entering mitosis and elongating when leaving mitosis, a cancer cell opens up room for its daughter cells in a crowded tumor. Thus, disrupting polar relaxation might curtail growth of cancer cells.
Although researchers have developed PP1 inhibitors, Baum says they might cause widespread side effects because the enzyme has many other functions. However, he notes that researchers might be able to design compounds that target PP1 or Sds22 bound to kinetochores.
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