Biology 441, Spring 2013: Lecture Notes on Cell Forces
Physical Forces: (Please read Chapter Eight of our textbook)
What forces create anatomical shapes and patterns?
→ NOT growth pressure, somewhat surprisingly!
→ Acto-myosin contraction. (Very important; and very diverse)
Invagination, Involution, Ingression.
Locomotion of cells and epithelial cell sheets.
Also inflating the eyeball, and the cornea.
The lower the tension, the more surfaces bulge out.
→ Electro-osmotic pressure. especially in Cartilage.
How does cytoplasmic actin exert traction forces by which tissue cells crawl (including tissue culture cells) ?
Most cell biology textbooks describe the "amoeboid" locomotion of body cells as if it were produced by protrusion of filopodia, attachment filopodia to some external object, and then contraction of the filopodia. This is supposed to pull the cell forward. It is a fiction; it doesn't happen. Just look at a time-lapse video of tissue culture cells and it is obvious that is not how they propel themselves. Unfortunately, the NIH has spent many millions of dollars for a large research program based on this fiction. It concentrates on identifying cytoplasmic proteins that become concentrated near the leading margins of fibroblasts and other tissue cells. These proteins are sure to be important, but it is impossible that they serve for force exertion by forward protrusion or rearward retraction of filopodia, since that method of cell propulsion is imaginary. Much direct evidence disproves that protrusion-retraction theory of cell motility. For example, retrograde transport of attached particles disproves that theory. Another disproof is the location where traction is exerted by cells crawling on flexible gels or thin sheets of rubber.
The actual mechanism of cell crawling if that cytoplasmic actin monomers assemble into fibers along the leading (front, but also rear) edges of a cell. These actin fibers flow "rearward" toward the center of the cell (nearer to the nucleus). Think of a tractor tread that is inside a large sack, and has to exert sideways forces through the material of this sack, from inside to outside. This sideways transmission of force is one of many phenomena that were made understandable by the Singer-Nicholson fluid-mosaic explanation of membrane structure. A chain of connected proteins, of which fibronectin and integrins are most important, transmit physical connections from the rearward-flowing actin fibers inside the cell to adhesions outside the cell.
Visualize a fleet of many submarines, all traveling along together in the same direction, with their periscopes sticking up through the surface. The submarines represent the moving actin fibers; Their periscopes represent the trans-membrane exertion of forces by integrins and fibronectin. Finally, visualize ice-bergs being pushed directionally across the ocean surface by sideways pressure of the the periscopes. You can hardly blame people for preferring to imagine that body cells crawl by a cycle of protrusion, attachment, and contraction of filopodia and other outward extensions of advancing cell margins. So what if that is inconsistent with where crawling cells exert forces, and contradicted by rearward transport of particles or any other movable object attached to the outside of the plasma membrane.
Please read the following excerpt from a review paper by Dr. Louise Cramer, a British Cell Biologist: (The entire paper is available on line, and conveys a (still-up-to-date!) good impression of the difficulties and debates about this subject. It will show you the need and opportunity for more research and careful thinking on this subject.)
[Frontiers in Bioscience, 2, d260-270, June 1, 1997]
MOLECULAR MECHANISM OF ACTIN-DEPENDENT RETROGRADE FLOW IN LAMELLIPODIA OF MOTILE CELLS
Louise P. Cramer
The Randall Institute, Kings College London, 26-29 Drury Lane, London WC2B 5RL, UK.
The following is a short quote from near the middle of Dr. Cramer's paper:
In this review, I will briefly describe the organization of actin filaments in leading edge structures of adherent, motilearrow to left) and lamella (dashed thick arrow to left), and recently, mostly cells, and in neuronal growth cones. Then, I will describe potential types of actin-dependent motile force to drive retrograde particle flow relative to the substratum in lamellipodia of these cells, and in growth cones of Aplysia neurons. I will present evidence in favor of each type of motile force, and discuss function of retrograde actin flow"...etc.
In conclusion, let's now briefly return, to the submarine & periscope analogy, regarding how actin fibers exert propulsive traction forces through the plasma membrane, from cytoplasm to extracellular objects. Several kinds of evidence indicate that the mechanical connection varies, somewhat as if the periscopes in the analogy attached and detached from their submarines. Although difficult to visualize, such variations should have been expected. After all, binding between all sorts of molecules is only temporary, with an equilibrium between bound and unbound molecules. Can you think of an example of molecular binding where that isn't true?
Please just give some thought to methods be which one could measure rates of turn-over in actin-external binding, through the plasma membrane. Wolpert himself has had some very clever ideas on this subject.
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