University of Massachusetts Amherst biologists Dominique Alfandari, Helene Cousin, and colleagues have identified unexpected and powerful cell-regulating functions in a protease known as ADAM 13, a discovery that holds promise for understanding tumor cell migration and the spread of cancer in the body.
The finding could also help identify genes active in such birth defects as cleft palate.
With support from the National Institutes of Health, the team has tracked individual cells in frog embryos to learn how the ADAM 13 protease controls proteins in the cranial neural crest to form the jaw and face. Cranial neural crest cell migration is common to all vertebrate embryos, including humans, and defects in their production or migration leads to severe facial malformations.
ADAM 13 belongs to a group of proteins called proteases that cut other proteins to change their function. Alfandari and colleagues' protein studies led them to discover a previously overlooked, "amazing" ability of ADAM 13 to direct cells to migrate. Once they understand how the protease functions, Alfandari adds, "anything we find can be adapted to cancer research. For example, this discovery may teach us how cancer cells migrate in the body to invade new organs. We may learn to prevent it."
He adds, "Medical research looks at proteins that are out of place. In cancer, they could be marking a tumor suppressor gene. And, many tumors use ADAM proteases to grow by stimulating blood flow or angiogenesis. They also help cells migrate from the original tumor site to create metastases."
Like others, the molecular biologist describes the two-part ADAM 13 protease as acting like a pair of scissors, with the blades always found at work on the outer surface of a cell and the handles always on the inside. Unlike the role of ADAM 13's extra-cellular segment in directing migration, activities of its counterpart inside the cytoplasm weren't noticed. "For the past 15 years, everybody thought that all the action was on the outer surface," Alfandari explains. "But our experiments changed that."
He and his colleagues were astonished to discover, in part by mutating ADAM 13, that the cytoplasmic, interior part took off in a new direction, went inside the cell nucleus and started to act totally independently. "A key experiment was when we expressed two different proteins, one corresponding to the cytoplasmic domain and the other to the extracellular domain, which showed that ADAM 13 was acting differently in the two areas," he says.
Further, this form of ADAM 13 activates the expression of genes related to its new identity, marking a complete role transformation. It's as if the scissor handle, when it reached the cell nucleus, suddenly changes itself into a cell phone, Alfandari suggests. "We used to think the part of proteases found in the cytoplasm was only important to control protease activity on the outside. Now we've shown that the inside part is different and can play an important role in development and regulation of cell function."
Alfandari and colleagues also point out that their experiments are particularly strong because they're carried out in individual cells in living frog embryos rather than isolated in plastic dishes. "We study the architecture in three dimensions and in living tissue, how it all fits and works in a real embryo. The holy grail is to understand gene function in real life."
The molecular biologist summarizes his laboratory's studies as "Like having all the parts of a car scattered in your backyard. Without the step-by-step instructions, you're never going to make a car from that heap of parts. Our work is to use all of the information available to understand how these individual cells come together to function and built something greater than the sum of the parts."
Illustration: ADAM 13. –University of Massachusetts.
University of Massachusetts Amherst News Release (02/14/11)
Abstract (Developmental Cell; Vol. 20, Issue 2, 256-263 (02/15/11))