Re: How are the activities of the cytoskeleton controlled and coordinated??

Hi Caron,

The question you pose is a very important one ...

I'll have to give you a little of the current thinking in the field, by no means has this been completely verified.

As you know the cytoskeleton is composed of three different filament systems : actin microfilaments , microtubules and intermediate filaments. These three filament systems join to form an intracellular meshwork which has a variety of functions. First, the cytoskeleton, as its name implies, constitutes a jellylike material within the cytoplasm which protects the cell from rupture due to external forces and helps maintain cell shape. This mechanical role extends to being able to detect forces and generate forces on the environment through molecular motors. Second, the cytoskeleton provides a set of tracks along which cellular cargoes can be trafficked. Motor proteins take cargoes from one part of the cell to the other and help maintain the positions of various organelles through the use of this 'highway' system. Thirdly, and the last one i'll describe, is the roles of the cytoskeleton in biochemistry in the cell. A large number of enzymes and other proteins reside permanently or transiently on the cytoskeleton. Some proteins are there to meet a substrate or other signalling molecule thereby localizing a reaction to a specific part of the cell. Other molecules reside on the cytoskeleton to be prevented from interacting with other molecules until they are released to do so.

The reason for this rather long introduction is to point out the rather vast set of functions the cytoskeleton has and how its 'regulation' could affect a variety of cellular functions. Regulation of the cytoskeleton, however, is thought to be due to four major molecular paradigms. The first is the role of calcium. Whether it is allowed in from the external environment or from intracellular stores, calcium has been shown to regulate a variety of proteins that directly bind the cytoskeleton often leading to local disruption of the cytoskeleton. For example, gelsolin, a microfilament severing protein, is actiavted by calcium to sever microfilaments in the cell to locally 'chop up' the actin cytoskeleton.

The second major molecular paradigm is the role of phosphorylation. A variety of protein kinases place phosphate groups on threonine, serine and tyrosine amino acids (available hydroxyl groups) and the phosphorylation of cytoskeletal proteins directly or of proteins that associate with the cytoskeleton can affect the structure and dynamics of the cytoskeleton. For example, during mitosis the intermediate filament are not required for cell division, so the intermediate filament system is extensively phosphorylated and then falls apart. After cell division is completed, the phosphate groups are removed by phosphatases and the intermediate filament system reforms.

A third molecular paradigm which is a hot current area of research are small GTP binding proteins, often called small GTPases. These proteins, of which the best known are Rac, Rho and cdc42, are thought to play important roles in the regulation of the cytoskeleton by influencing the structure and dynamics of the cytoskeletal filaments, particularily actin.

Finally, a fourth big player are the polyphosphoinositol lipids. These phospholipids (ones with an inositol group in the hydrophilic region) have been shown to interact directly with a number of cytoskeletal associated proteins (e.g. gelsolin - microfilament severing protein, intermediate filaments directly, and tau, a microtubule associated protein) that help maintain structure and dynamics. This work is currently being evaluated in the cellular context, and much of the original biochemical work was done by Prof. Paul Janmey (my advisor).

Note that all four of these mechanisms have a great deal of interplay, so that calcium could give rise to a number of other signals which result in activation of small GTPase, production of inositol phospholipids and protein phosphorylation.

So as you can see, this is a very generic view of the major molecular mechanisms that we believe underlie the control and coordination of the cytoskeleton. I have kept the discussion sufficiently general so as not implicate any particular cytoskeletal system, but all the cytoskeletal systems have been implicated in each of these paradigms. One aspect I have left out, because it is the sole subject of many books, is the spatiotemporal control of cytoskeletal regulation. That is, given the molecular mechanisms outlined above, how does the cell respond in time and space to a particular extracellular cue that is directional in nature. For example when a white blood cell detects a bacterium it must engage its machinery to crawl (a cytoskeletal event) towards the bacterium, then engulf the bacterium. All these function require meticulous coordination of all three cytoskeletal systems in particular places and times within the cell. Much of this work is still being worked out, much like the molecular details I mentioned above.