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Cell Motility

Cells need to generate and regulate contractile forces in order to efficiently move in physiological conditions, to maintain proper cellular polarity, and, in certain cases, to direct cell differentiation. The underlying processes of force generation rely upon the coordination of a number of cellular signaling mechanisms which ultimately function to allow cells to undergo protrusion at the leading edge and retraction at the rear edge. In this way intracellular force generation, in part directed by biochemical and mechanical signals from the extracellular matrix, functions to ultimately direct both cell form and function in vivo.

In order to properly coordinate cellular movement, cells need to be able to generate contractile forces which will allow the rear edge of the cell to retract following the protrusion of the leading edge of the cell. These forces stem from the manipulation of the actin cytoskeleton in such a way as to promote this movement, with the actin binding protein myosin II serving as a major regulator of contractility. On the individual protein level, myosin II proteins bind multiple actin filaments and deform them in such a way that areas containing large amounts of myosin II form increasingly compressed actin networks As a result, the actin network as a whole tends to undergo significant compression toward the rear of the cell where there is a high local concentration of myosin II. As this network compresses cells tend to contract, resulting in a retraction of the cell at the myosin II-rich rear edge where adhesive forces are not as strong as contractile forces, but protrusion of the cell at the myosin II-poor leading edge where adhesive forces are stronger than contractile forces. In this way, the activities and localization of single proteins can bring about cell-wide alterations in contractile force generation and cell dynamics.

Signaling Components

In order to maintain these areas of localized linked contractility and protrusion necessary for motility to occur, cells must regulate myosin II and related signaling activities. This regulation is largely carried out by protein members of the family of Rho GTPases – primarily Rac, RhoA, and Cdc42. These small GTPases act sequentially in motile cells, with their areas of activity being separated both spatially and temporally resulting in coordinated cyclic cell movement. Cdc42 is first activated at the leading edge of the cell following the transduction of a signal from a chemoattractant or other source. Active Cdc42 activates WASp/PIP2 and Rac, both of which activate Arp2/3 resulting in additional polymerization of actin at the site of Cdc42 activation. This leads to the growth of filopodia and lamellipodia and the localized inhibition of contractility at the leading edge of the cell, allowing for protrusion to occur RhoA is then activated at the rear edge of the cell where it promotes stress fiber formation due to the inhibition of Rac and the activation of myosin II following phosphorylation of the myosin II light chain. Activated myosin II promotes the contraction of the rear portion of the cell, resulting in the net movement of the cell towards the chemoattractant.

Rac activity additionally promotes the dephosphorylation of the myosin II light chain, thereby inhibiting contraction of the leading edge of the cell, further promoting protrusion. By regulating myosin II and Arp2/3 activity in this way, cells are able to maintain separate areas of near-simultaneous contraction and protrusion which are integral to proper cell movement and functionality.

The localized regulation of Rho GTPases based on biochemical and mechanosensing signals is a complex process; one crucial protein involved in this process is focal adhesion kinase (FAK). When cells begin to form focal adhesions at the leading edge following the binding of integrin proteins to the ECM, FAK is recruited to these adhesions where it results in further integrin activation and the net strengthening of cellular adhesions. FAK is also required for cells to properly transduce signals from extracellular mechanical stimuli, with FAK activity being necessary for tension-mediated strengthing of focal adhesions. FAK has additionally been shown to serve as both an activator and a regulator of both Rac and RhoA via its regulation of a number of guanine exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs and GAPs coordinate the activation of the Rho GTPase proteins, thereby allowing FAK activity to directly modulate the cyclic nature of contractile force generation in response to extracellular stimuli. Unsurprisingly, FAK-null cells experience serious disruptions in motility, further underscoring the importance of FAK regulation for cells to be normally motile.

Surface Requirements

Cells will only be motile on substrata of appropriate rigidity whereupon they achieve adhesions of an optimum strength. If cells which are normally present on a rigid surface are transferred to a soft surface, they will not be able to spread effectively due to the cells’ inappropriately strong adhesions, which will deform the ECM and prevent normal cell movement. This demonstrates the fact that cells need to be well suited to their environment in order to properly function. Indeed, cancer cells often misregulate FAK and related adhesion proteins which allows them to invade tissues wherein they would not normally be able to spread, further confirming the importance of proper reciprocal mechanosignaling.

While cell functionality often relies upon appropriate surface rigidity, surface rigidity can also alter cell function, particularly in stem cells. For example, when naïve mesenchymal stem cells are incubated on soft, intermediate, or stiff surfaces, they develop phenotypes similar to neurons, myoblasts, or osteoblasts respectively. These changes in phenotype stem from widespread changes in gene expression as a result of surface rigidity, and this study demonstrates a positive linear correlation between surface rigidity and tension within cells. All of these effects can be eliminated by first treating cells with blebbistatin in order to inhibit myosin II activity, pointing to the importance of proper contractility in this process of cell fate determination. In summation, these results clearly illustrate the fact that while cells rely upon a proper match between cell adhesiveness and surface rigidity in order to function, the rigidity of the surface can also have a drastic impact upon cell form and function, confirming that proper mechanosensing is vital to processes beyond simply cell motility in vivo.

Mechanosensing

In order to function efficiently, cells need to respond to external stimuli by coordinating contractile and protrusive forces in order to achieve cell movement and differentiation. This feat relies upon the localized generation of cytoskeletal compression by myosin II which, via Rho/Rac/Cdc42-mediated signaling, allows highly motile cells to protrude at the leading edge and retract at the rear nearly simultaneously. The expression of these Rho GTPases is in part regulated by FAK-mediated mechanosensing, allowing extracellular signals generated based on the rigidity of the surface to which the cell is attached to alter cell motility and activity. Additionally, in undifferentiated stem cells mechanosignaling is able to direct differentiation of cells into different phenotypes based solely upon differences in surface rigidity. These results ultimately confirm the physiological importance of contractile force generation and mechanosensing to both cellular form and function.

References

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