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Getting the message from cell to cell

Cooper lab uncovers previously unknown role for lipoprotein receptors; could shed light on cell corruptions that lead to disease
Dr. Darren Kamikura
Dr. Darren Kamikura examines embryos of the worm C. elegans in Dr. Jonathan Cooper's lab. Their recent study found that proteins called lipoprotein receptors export signals important for the worm's normal development. Photo by Todd McNaught

Effective human communication requires some basic principles for success. A clear message must be crafted by the sender, delivered at the appropriate place and time and interpreted correctly by the recipient.

The same fundamentals apply to communication among and within cells of all living creatures. For example, the successful relay of molecules contributes to the transformation of a fertilized egg into a mature animal.

A recent Basic Sciences Division study of one type of biological communication in the tiny soil worm Caenorhabiditis elegans now adds a new twist to an already complex process. Postdoc Dr. Darren Kamikura and Dr. Jon Cooper have found that proteins once thought to import molecules into the cell can, in some situations, act as message senders.

In the Nov. 15 issue of Genes and Development, the researchers report that the release of a cellular message required for normal development depends on proteins previously thought mainly to import nutrients into cells. They conclude that these proteins-called lipoprotein receptors-have a second role to play in secretion, the process by which proteins are transported out of a cell. Without proper message export at the correct time, the message-receiving cells cannot respond.

"Lipoprotein receptors are normally thought of as bringing molecular messages into cells, although recently, they've been suspected of transporting molecules within cells too," Kamikura said. "But this is the first evidence that they are also important for secretion."

The same phenomenon may also exist in other organisms including humans, since counterparts of the lipoprotein receptors are found widely in nature. If so, the new results could someday help scientists better understand and possibly fix corrupted communication pathways that lead to cancer and other diseases.

Lipoprotein receptors are best known for enabling cells to take up cholesterol from the blood. Defective receptors cause a condition that leads to excess buildup of cholesterol in the blood, which causes heart disease. Related proteins in many animals have now been found to be important for cells to take up a variety of molecules, including signals required for normal development.

'Disabled' protein clues

Kamikura and Cooper's identification of a new function for lipoprotein receptors in the worm was prompted by their analysis of another protein known as "Disabled." Named for the role of its counterpart in mice in normal brain development, the Disabled protein assists lipoprotein receptors in transmission of signals into cells.

The researchers found that worms lacking Disabled were impaired in their ability to lay eggs. Successful egg-laying depends on the proper formation and positioning of multiple parts of the animal. One step in the process involves the movement of specialized muscle cells from one part of the worm to the sex organs. The movement is prompted by the release of a protein signal from the sex organs to the muscle cells. The protein signal attracts the cells to their correct destination.

The researchers first had to determine which aspect of the egg laying was compromised in the worms that lacked Disabled, Kamikura said. "It could have been that the lack of Disabled prevented the muscle cells from migrating to the sex organ. Another possibility was that it interfered with connections of nerves to the sex organ."

Their experiments showed that the egg-laying defect in worms that lack Disabled protein was caused by ineffective muscle-cell migration due to the inability of the sex organ to release, or secrete, the migration signal. Further analysis showed that Disabled must partner with two lipoprotein receptors in the worm to coordinate release of the signal, a protein called FGF.

Kamikura is now trying to determine whether an analogous process takes place in human cells. He's also curious about whether Disabled and its various lipoprotein receptor partners have a widespread role in the secretion of signaling molecules in many organisms. In humans, FGF signals from tumors can trigger new blood vessels to form, which supply the cancer with both added nutrients needed for rapid growth and the highway with which to spread.

"We don't yet know if our findings will hold true for other organisms," he said. "But obviously there would be great interest in finding ways to manipulate the process and possibly slow the growth or spread of tumors."

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