Mechanical Signaling Mechanisms

But how do changes in ECM mechanics or in the level of tractional forces cells exert on their focal adhesions influence cell motility? Focal adhesions are critical to the migratory process because they are sites of attachment between the ECM, transmembrane adhesion receptors (known as integrins), and the actin cytoskeleton, which stabilize lamel-

lipodia and transmit propulsive forces. In addition, the cytoskeletal backbone of the focal adhesion acts as an orienting scaffold for a vast array of signaling molecules. They also are sites where the mechanical and biochemical signals that regulate cell migration are integrated inside the cell.

The temporal and spatial organization of focal adhesion assembly is only partially understood; nevertheless, it is clear that physical forces significantly impact this process. The application of force to newly formed integrin-cytoskeleton linkages promotes additional focal adhesion assembly, and hence mechanically reinforces the connection, by inducing force-dependent signaling events inside the cell. For example, cytoskeletal tension exerted on the ECM via new adhesion sites results in the maturation of small nascent adhesive contacts ("focal adhesion complexes") into larger, more highly organized anchoring structures (classic "focal adhesions"). The earliest events in the assembly process include activation of receptor and nonreceptor tyrosine phosphatases, and the subsequent sequential recruitment of talin and paxillin, followed by slower recruitment of vinculin and FAK. The presence of tensin and zyxin may indicate a late stage of adhesion assembly or a transition to a different type of adhesion site that assembles only after the leading edge has stabilized.

To date, more than 50 different signaling molecules have been reported to be associated with focal adhesion sites, and further investigation into the functional consequences of this molecular heterogeneity is ongoing. In addition, the dynamic aspect of adhesion assembly and disassembly will need to be examined in the future. The lifetime of an adhesion is on the order of tens of minutes, whereas the exchange rates of its individual structural components appear to be on the order of seconds to minutes. The local mechanical compliance of the ECM also may spatially regulate the strength, size, number, and molecular composition of the cell-ECM adhesions, and thus it may be a major source of spatial heterogeneity in adhesion complexes. For example, treatment of cells with HL-7 to inhibit actomyosin contractility results in the rapid loss of phosphotyorosine from focal adhesions, followed by disassembly of the complex on a slower time scale. These findings suggest that tension applied through the actomyosin system may trigger local tyrosine phosphorylation events that are required for the subsequent assembly of adhesion complexes.

Micromanipulation studies utilizing magnetic or optical micromanipulation techniques have unequivocally demonstrated that changes in the balance of forces transmitted across cell surface integrins play a key role in organization of the focal adhesions that mediate cell motility. Application of physical stresses to integrins results in the recruitment of focal adhesion proteins, actin filaments, signaling molecules, and mRNA to the site of force application. Focal adhesions also respond rapidly to mechanical perturbations and may actively regulate their dynamics to control their strength, size, and spatial distribution. For example, application of fluid shear stresses to the apical membranes of confluent endothelium results in almost immediate focal adhesion remodeling at the cell base, with preferential addition of new components in the direction of the applied stress.

It is now clear that directed motility within developing tissues, such as vascular networks, is controlled by local changes in cellular force balance. Mechanical perturbation of tissues or their underlying ECM results in the transmission of forces across integrin receptors, restructuring of the CSK, and activation of various signal transduction cascades in a force-dependent manner. Recent work in Drosophila has confirmed that the migratory motion of cell layers similarly generates mechanical forces that shape the digestive tract. During development of this tissue, movements of the posterior and anterior mesoderm cells compress neighboring stro-modeal precursor cells. This mechanical stress results in the translocation of Armadillo transcription factor to the nucleus, where it upregulates expression of Twist, a gene required for invagination of the stromodeum. In cells expressing a mutant form of Twist, these events can be rescued by the application of an external mechanical force (using a micropipette). Thus, mechanical force per se clearly can impact cell migration in a developmentally relevant way.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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