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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Oct 24, 2013

 

Diagram of a hand-like or "claw" projection (left) versus the "ruffling" of the cell membrane (right) that occur with and without the activation of the messenger protein network.

Image Credit: Devreotes Lab

 







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Cell movement directed by two types of proteins

Cell biologists have teased apart two pieces of the cell machinery that gets cells to move. Cell projections that act like hands to help a cell "crawl," must be initiated by a protein network inside the cell that can also make it "ruffle" or move spontaneously.


It was already known that cell movement results from a message-relaying network of proteins, activated by sensor proteins on a cell's surface in response to external cues.

They now know that in random movement, the messenger network can self-activate — spontaneously by "ruffling."


Because cell movement is necessary for everything from embryo development, to wound healing, to cancer metastasis, the work is expected to have wide-ranging implications for understanding and manipulating these processes. In fact, the researchers note that defects in the messenger protein network have been linked to many types of cancer.

Their findings are summarized in a paper published online Oct. 20 in the journal Nature Cell Biology.

"It was previously thought that messenger proteins were only involved in directional movement: that without them, cells could only move randomly, through the spontaneous formation of these hand-like projections," says Peter Devreotes, Ph.D., professor and director of the Department of Cell Biology at the Johns Hopkins University School of Medicine. "Now we know that even random movement requires the activation of the messenger protein network."

According to Devreotes, a key component of a cell's machinery is a crisscrossing network of protein chains that wrap around the inside edge of the cell, giving it shape and structure and inspiring the name "cytoskeleton." To allow movement, this network must build itself up in a given area of the cell, pushing the cell's membrane outward and creating a hand-like projection that can "grip" the external environment and pull the cell forward.

The cytoskeleton, Devreotes says, takes orders from the messenger protein network, which is connected to sensor proteins on the outside of the cell. The sensors detect directional signals coming from other parts of the body and pass them on to the messenger proteins, which in turn call on the cytoskeletal proteins to create a projection in the right direction.

In their experiments, the Devreotes team sought to understand the relationship between each of these components. They began, he says, by bathing their cells in a drug that paralyzes the cytoskeleton. Not surprisingly, the cells wouldn't move, but the spontaneous responses of the messenger network still occurred.


"You can think of the cell as a row boat with several crewmen and a coxswain, sitting in the rear, steering the rudder and shouting at the crew to keep their movements in sync. If the oars are taken away (i.e., a paralyzed cytoskeleton), the coxswain can yell at the crew as much as he wants but the boat won't move."

Peter Devreotes, Ph.D., professor and director of the Department of Cell Biology at the Johns Hopkins University School of Medicine


Using a combination of genetic and imaging techniques, the team then incapacitated the other components of the system one by one and watched what happened. Inhibiting the messenger proteins (the coxswain) showed that the cytoskeleton has an intrinsic rhythm that "ruffles" the cell membrane every 10 seconds, but there were no projections created, so the cells didn't move. "It's as if the crew can still row without the coxswain but each person is rowing in a different direction so the boat just stays where it is," says Chuan-Hsiang Huang, a co-author of the study.

The team expected that when they removed the sensor proteins they would see no movement, based on the old idea that both random and directional cell movement required signaling from these proteins. However, they found instead that the messenger network is "excitable." That is, without the sensor proteins or external cues, the messenger proteins can still work on their own, telling the cytoskeleton to create projections here or there, moving the cells about randomly.

"This situation could be compared to a boat without a rudder. The coxswain is there to coordinate the rowing of the crew so the boat does move, but not in any specific direction," explained co-author Ming Tang.


Devreotes feels the most exciting implications of this research are those relevant to cancer metastasis.

"Several of the messenger proteins that we studied are found in higher quantities during cancer progression, and it is likely that the resulting changes in cell movement are involved in the advancement of the disease. We now know that we have to create drugs that target the messenger proteins (not just the sensor proteins) in order to entirely immobilize tumor cells."


Abstract
It is generally believed that cytoskeletal activities drive random cell migration, whereas signal transduction events initiated by receptors regulate the cytoskeleton to guide cells. However, we find that the cytoskeletal network, involving SCAR/WAVE, Arp 2/3 and actin-binding proteins, is capable of generating only rapid oscillations and undulations of the cell boundary. The signal transduction network, comprising multiple pathways that include Ras GTPases, PI(3)K and Rac GTPases, is required to generate the sustained protrusions of migrating cells. The signal transduction network is excitable, exhibiting wave propagation, refractoriness and maximal response to suprathreshold stimuli, even in the absence of the cytoskeleton. We suggest that cell motility results from coupling of ‘pacemaker’ signal transduction and ‘idling motor’ cytoskeletal networks, and various guidance cues that modulate the threshold for triggering signal transduction events are integrated to control the mode and direction of migration.


The other authors of the report are Changji Shi and Pablo Iglesias of The Johns Hopkins University.

This work was supported by grants from the National Institute of General Medical Sciences (GM28007, GM34933, GM71920) and the Damon Runyon Cancer Research Foundation.

Original press release:http://www.eurekalert.org/pub_releases/2013-10/jhm-cm101713.php