A moving fibroblast (connective tissue cells) displays a characteristic sequence of events:
- initial extension of a membrane protrusion
- attachment to the substratum
- forward flow of cytosol
- retraction of the rear of the cell
These events occur in an ordered pattern in a slowly moving cell such as a fibroblast, but rapidly moving cells, such as macrophages, all of them are occurring simultaneously in a coordinated manner. We first consider the role of the actin cytoskeleton, and then the involvement of the endocytic cycle.
Membrane extension
The network of actin filaments at the leading edge is a type of cellular engine that pushes the membrane forward in a manner very similar to the propulsion of Listeria by actin polymerization. Thus at the membrane of the leading edge, actin is nucleated by the activated Arp2/3 complex and filaments are elongated by assembly onto (+) ends adjacent to the plasma membrane.
As the actin meshwork is fixed with respect to the substratum, the front membrane is pushed out as the filaments elongated. This is vey similar to Listeria, which “rides” on the polymerizing actin tail, which is also fixed within the cytoplasm. Actin turnover, and thus treadmiling, is mediated, as it is in the comet tails of Listeria, by the action of profilin and cofilin.
Cell-substrate adhesions
When the membrane has been extended and the cytoskeleton has been assembled, the plasma membrane becomes firmly attached to the substratum. Time-lapse microscopy shows that actin bundles in the leading edge become anchored to the structures known as focal adhesions.
The attachment serves 2 purposes:
- it prevents the leading lamella from retracting
- it attaches the cells to the substratum, allowing the cell to move forward.
Given the importance of focal adhesions and their regulation during cells locomotion, it is not surprising that they have been found to be rich in molecules involved in signal-transduction pathways.
The cell-adhesion molecules that mediate most cell-matrix interactions are membrane proteins called integrins. These proteins have an external domain that binds to specific components of the ECM, such as fibronectin and collagen, and a cytoplasmic domain that links them to the actin cytoskeleton.
The cell makes attachments at the front, and as the cell migrates forward, the adhesions eventually assume positions toward the back.
Cell-body translocation
After the forward attachments have been made, the bulk contents of the cell body are translocated forward. It believed that the nucleus and the other organelles embedded in the cytoskeleton are moved forward by myosin II-dependent cortical contraction in the rear part of the cell, like squeezing the lower half of the tube of toothpaste. Consistent with this model, myosin II is localized to the rear cell cortex.
Breaking cell attachments
Finally, in the last step of movement (de-adhesion), the focal adhesions at the rear of the cell are broken, the integrins recycled, and the freed tail brought forward. In the light microscope, the tail is often seen to “snap” loose from its connections- perhaps by the contraction of stress fibers in the tail or by elastic tension- and it sometimes leaves a little bit of its membrane behind, still firmly attached to the substratum.
Cells cannot move if they are either too strongly attached or not attached to a surface. The ability of a cell to move corresponds to a balance between the mechanical forces generated by the cytoskeleton and the resisting forces generated by cell adhesions. This relationship can demonstrated by measuring the rate of movement in cells that express varying levels of integrins. Such measurements show that the fastest migration occurs at an intermediate level of adhesion, with the rate of movement falling off at high and low levels of adhesion. Cell locomation thus results from traction forces exerted by the cell on the underlying substratum.
Recycling membrane and integrins by endocytosis
The dynamic changes in the actin cytoskeleton alone are not sufficient to drive cell migration; it is also dependent on endocytic recycling of membranes. The membrane needed during lamellipodium extension is provided by internal endosomes following their exocytosis.
Adhesion molecules in focal adhesions at the rear of the cell are internalized as those adhesions are disassembled and transported by an endocytic cycle to the front to make new substratum attachments.
This cycling of adhesion molecules in a migrating cell resembles the way a tank uses its treads to move forward. The movement of membrane internally through the cell also generates a rearward membrane flow across the surface of the cell.
Indeed, this type of flow may contribute to the mechanics of cell locomotion, as it has recently been found that white blood cells can move in a liquid (“swim”) in the absence of attachment to a substratum, presumably as surface structures operating like paddles move backward across the cell surface.
Retype from Lodish 8th Edition, p.811
Genome 4 