Cadherin-catenin-actin structure exerts force inside and between cells in living tissues, study shows

July 16, 2012
Proposed model: Cadherins (orange bars) are under tension generated by actomyosin and mediated by catenins (alpha and beta). Credit: Alexander Dunn, Stanford School of Engineering

If you place certain types of living cells on a microscope slide, the cells will inch across the glass, find their neighbors, and assemble themselves into a simple, if primitive tissue. A new study at Stanford University may help explain this phenomenon, and then some, about the mechanical structure and behavior of complex living organisms.

In the paper published in the , Alexander Dunn, PhD, and a multidisciplinary team of researchers in biology, physiology, and chemical and , were able to measure—and to literally see—the at play between and within the living .

There are scads of data explaining chemical signaling between cells. "And yet, one of the great roadblocks to a complete knowledge of how cells work together to form tissues, organs and, ultimately, us, is an understanding of the mechanical forces at play between and within cells," said Dunn.

Using a new force-sensing technique, Dunn and team have been able to see mechanical forces at work inside living cells to understand how cells connect to one another and how individual cells control their own shape and movement within larger tissues.

Pulling back the veil on the exact nature of this mechanism could have bearing on biological understanding ranging from how tissues and tumors form and grow, to the creation of entire complex .

The video will load shortly.
This brief video shows a cell division within a tissue and the mechanical forces clearly at play in the cell's placement in the tissue. Credit: Alexander Dunn, Stanford School of Engineering

Seeing the force

"Cells are really just machines. Small, incredibly complex biological machines, but machines nonetheless," said Dunn. "They rely on thousands of moving parts that give the cell shape and control of its destiny."

The mechanical parts are proteins whose exact functions often remain a mystery, but Dunn and team have helped explain the behaviors of a few.

At its most basic level, a cell is like a balloon filled with saltwater, Dunn explained. The exterior of the cell, the balloon part, is known as the membrane. Protruding through the membrane, with portions both inside and outside the cell, are certain proteins called cadherins.

Outside of the cell, cadherins bind one cell to its neighbors like Velcro. The 'herin' portion of the name, in fact, shares a Latin root with "adhere."

On the inside of the cell, cadherin is connected to long fibers of actin and myosin that stretch from membrane to nucleus to membrane again. Actin and myosin work together as the muscle of the cell, providing tension that gives the cell shape and the ability to control its own movement. Without this force, the balloon of the cell would be a shapeless, immobile blob.

Puppeteer's string

"If you watch a cell moving across a glass slide, you can see it attach itself on one side of the cell and detach on the other, which causes a contraction that allows the cell to, bit by bit, pull itself from place to place," said Dunn. "It's clearly moving itself."

While it was understood that cadherin and actin are connected to one another by other proteins known as catenins, what was not known was how, when, and where the cells might be using their muscles (actin and myosin) to tug on the Velcro (cadherin) that holds them to other cells.

This is an important problem in the development of organisms, since a cell must somehow control its shape and its attachments to other cells as it grows, divides, and migrates from one place to another within the tissue. Dunn and his colleagues have shown that the actin-catenin-cadherin structure transmits force within the cell and, further, that cadherin can convey mechanical forces from one cell to the next.

It is a form of mechanical communication, like the strings of a puppeteer. Dunn and others in the field believe that these mechanical forces may be important in conveying to a cell how to position itself within a tissue, when to reproduce and when to stop as the tissue reaches its proper size and shape.

"That is the theory, but an important piece was missing," said Dunn. "Our research shows that forces at cell-cell contacts can in fact be communicated from one cell to its neighbors. The theorized mechanical signaling mechanism is feasible."

Story within a story

How Dunn and his colleagues got to this point is a story in itself. It reads like the recipe for a witch's potion—cultured canine kidney cells, DNA from jellyfish and spider silk, and microscopic glass needles.

To measure the force between cells, a team combining the skill of several Stanford laboratories—headed by Professor Dunn in chemical engineering, professors William Weis and W. James Nelson in the Department of Molecular and Cellular and associate professor of mechanical engineering Beth Pruitt—used a tiny and ingenious molecular force sensor developed by Martin Schwartz and colleagues at the University of Virginia. The sensor combines fluorescent proteins from jellyfish with a springy protein from spider silk.

The genes for the sensor are incorporated into the cell's DNA. Under illumination, the cells glow in varying colors depending on how much stretch the sensor is under. In this study, the force sensor is inserted into the cadherin molecules—when the Velcro stretches, so does the sensor.

The team then took things a step further. By turning the activity of myosin, actin and catenin on and off, they were able to determine that these proteins are in fact linked together and are at the heart of inter- and intra-cellular mechanical force transmission.

Lastly, using glass microneedles, the team tugged at connected pairs of cells, pulling at one cell to show that force gets communicated to the other through the cadherin interface.

"At this point we now know that a cell exerts exquisite control over the balance of its internal forces and can detect force exerted from outside by its neighbors, but we still know next to nothing about how," said Dunn. "We are extremely curious to find out more."

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Jul 16, 2012
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Jul 16, 2012
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5 / 5 (7) Jul 16, 2012
I would think that after all this time and hundreds if not thousands of comments that clearly violate the Comments guildlines, kevinrts would be banned. I know he would be back under a new name, but diligent reporting will quickly get him banned again if people and the moderators are a little on their toes.

I am sick and tired of hearing kevinrts running on and on about his cult and their bizarre belief system.
4 / 5 (2) Jul 16, 2012
How does one explain that all of this got together by sheer random accident
One does NOT explain it by sheer random accident. Certain molecules have TENDENCIES to combine in certain ways, rather than assembling themselves by random collision (Hoyle's silly "tornado in a junkyard" image). When a system has an inbuilt tendency, the influence of randomness can be greatly diminished. It's rather like playing with loaded dice.
"Now, how and why did these molecules get such tendencies?" you may ask. Perhaps THAT is in the realm of some Designer.
All we can honestly say, as of yet, is "insufficient data"--but we're gathering as much data as we can, as quickly as we can. "Watch this space," as they say.

trying to figure out how nano-newton forces can be detected, transmitted and understood by such fragile biological components?
It may well be that such components are not as fragile as you imagine, on their own scale. Nanonewtons are apparently well within their capacity.
5 / 5 (2) Jul 17, 2012
Why isn't kevin banned? I remember getting warnings for being off-topic once or twice, but completely irrelevant creationist blathering is all he does.
5 / 5 (2) Jul 17, 2012
You should do what you can http://www.change...-program
5 / 5 (3) Jul 17, 2012
Big fucking surprise. My comment telling the staff to do their job that should have been done years ago was deleted.

5 / 5 (2) Jul 19, 2012
This is very exciting research. The evolved ability to form tissue is what distinguish animals above the early branching of sponges to form complex behavior.

The most deep divergence where something similar have evolved is in slime molds, before animals diverged, and they use the same components. Turns out that slime mold fruiting bodies makes an epithelium analog in the growing stalk, with a connecting substrate of exuded cellulose (which animals can grow too) and proteins in the center. It is hence oriented (polarized) by having inner and outer surface.

"A polarized epithelium in the non-metazoan Dictyostelium discoideum requires -catenin and -catenin but not classical cadherins, polarity proteins or Wnt signaling."

5 / 5 (1) Jul 19, 2012
As always, creationists shouldn't comment on science, it is laughable.

It is biology that explains how functions of biological machines appear over deep time by observed evolution. Science has known this biology for almost two centuries, and by its complexity it is the most tested and well established area (fact and theory) of all of science.

Magical poofing out of nowhere has as much credibility as astrology. It can't explain any of this, no mechanism, but a contender would have to explain as much and more.

@ aroc91:

Of course the hit-and-run tactics of trolls are telling. If it looks like a duck, swims like a duck, and quacks like a duck, then it probably is a duck.

Presumably he gets paid for his persistence or he is more nuts than the usual science denialists. In either case he makes a very good case for the problems with religion. And he is fun to watch too, as he swims in shit for ideas and quacks inanities.
5 / 5 (1) Jul 19, 2012
Oops, html fail. Modified for legibility:

"A polarized epithelium in the non-metazoan Dictyostelium discoideum requires Alfa-catenin and Beta-catenin but not classical cadherins, polarity proteins or Wnt signaling."
not rated yet Jul 22, 2012
Small, incredibly complex biological machines

Our research shows that forces at cell-cell contacts can in fact be communicated from one cell to its neighbors. The theorized mechanical signaling mechanism is feasible

At this point we now know that a cell exerts exquisite control over the balance of its internal forces and can detect force exerted from outside by its neighbors, but we still know next to nothing about how

If it walks like a duck, looks like a duck and quacks like a duck, eats like duck, eventually you have to come to the conclusion that it IS a duck.
How does one explain that all of this got together by sheer random accident when here we have the researchers in a tizzle trying to figure out how nano-newton forces can be detected, transmitted and understood by such fragile biological components?

Doesn't matter how much we learn, you would say, see, that bit left over proves my god did it all. You are a sick person.
not rated yet Jul 22, 2012
PNAS articles of Dunn's research group: 1, 2

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