Microtubule Dynamics


Manu Lopus, Mythili Yenjerla and Leslie Wilson, Department of Molecular, Cellular, and Developmental Biology and The Neuroscience Research Institute, University of California, Santa Barbara, California

doi: 10.1002/9780470048672.wecb338


Microtubules are cylindrical, cytoskeletal protein polymers found in all eukaryotic cells. They perform a plethora of functions associated with cellular structure, organization, and movement. They polymerize and depolymerize by the reversible addition and loss of α:β tubulin heterodimers, which are their building block subunits, at the microtubule ends. Importantly, microtubules are not simple equilibrium polymers. The hydrolysis of GTP that occurs when tubulin dimers add to the ends of microtubules creates two distinct and often coexisting dynamic behaviors: dynamic instability and treadmilling. These dynamic properties are crucial in guaranteeing the faithful segregation of chromosomes during cell division, in many kinds of intracellular transport, in cell signaling, and even during programmed cell death. Microtubule dynamics play critical roles in terminally differentiated cells as well. In neurons, microtubule dynamics regulate neuronal plasticity, growth-cone motility, and maintenance of mature neurons. Suppression of mitotic spindle microtubule dynamics by small drug molecules is an important therapeutic strategy for treatment of many types of cancer. In addition, agents that stabilize microtubule dynamics offer potential for treating neurodegenerative diseases in which the dynamics are misregulated. Agents that modulate microtubule dynamics can be used as experimental tools or could be used therapeutically to perturb the functions of any cellular disease processes dependent on the dynamics.


This review focuses on the dynamic behaviors of microtubules. Because of space limitations, we concentrate on the molecular, mechanistic, and kinetic aspects of microtubule dynamics, their significance and regulation in dividing cells, and how microtubule-targeted drugs that modulate microtubule dynamics act to inhibit mitosis and kill tumor cells. It is an extensive and rich area of research; thus we must direct the reader to the cited literature including the Further Reading list for a more thorough coverage of the field.


General Features of Microtubule Structure and Polymerization

Microtubules are physically robust, dynamic, cylindrical, cytoskeletal polymers (Fig. 1) composed of the protein tubulin, which is a heterodimer that consists of one alpha and one beta subunit. The structural, mechanical, and polymerization properties of microtubules are essential for normal cell division, for development and maintenance of cell structure, for many kinds of intracellular transport, for positioning of intracellular organelles, and for programmed cell death (reviewed in References 1 and 2). Microtubules polymerize and depolymerize by the reversible noncovalent addition and loss of α:β tubulin dimers at their ends. The orientation of α:β tubulin dimers in the microtubule provides the polymer with structural and kinetic polarity, with the end designated as the plus end, where h-tubulin is exposed, being relatively more dynamic than the opposite or minus end, where a-tubulin is exposed. The opposite ends of microtubules exhibit remarkably different behaviors. For example, during assembly of microtubules, tubulin polymerizes more rapidly at plus ends than at minus ends. Also, as described in more detail below, the plus ends alternate between phases of growth and shortening more frequently and fluctuate in length to a greater extent than the minus ends (3).

The self-assembly of tubulin to form microtubules was described initially in a classic polymerization model of nucleated helical polymerization by Maruyama and Oosawa (4). Assembly involves two phases: a nucleation phase followed by an elongation phase. With purified systems in vitro, nucleation can be achieved in several ways, such as by inclusion in polymerization reactions of various stabilizing microtubule-associated proteins (MAPs), by using preformed microtubule seeds prepared either by shearing preformed microtubules through a 25 gauge needle or by using sea urchin axonemes (5). The nucleation of tubulin assembly in vitro also can be achieved with microtubule-stabilizing chemical substances such as glutamate, dimethyl sulfoxide, and glycerol (6).

Microtubule assembly in cells differs in some ways from assembly in vitro. In cells, nucleation of microtubules requires a third type of tubulin, which is called γ-tubulin, that functions in concert with other proteins in the form of a γ-tubulin ring complex. In most animal cells, the y-tubulin ring complex is located at the pericentriolar region of the microtubule organizing center (or centrosome) where it nucleates microtubule assembly at the minus ends (7). The γ-tubulin does not become incorporated into the microtubule, but rather it only localizes to the minus ends. Assembly of tubulin to form microtubules during the early stages of polymerization in vitro can be considered a pseudo first-order reaction. A steady state is eventually attained in which both the soluble tubulin concentration and the microtubule polymer mass attain stable plateaus (8). The critical concentration at apparent equilibrium (actually a steady state, see below) is the concentration of soluble tubulin in apparent equilibrium with the microtubule polymers.

The assembly of tubulin to form functional microtubules is a complex process (see References 2, 8, and 9). Two GTP binding sites are on the tubulin dimer: One is on β-tubulin, which is readily exchangeable when the tubulin is in solution, and the other on α-tubulin, which is not exchangeable, located at the interface between α- and β-tubulin (1). The GTP bound to the exchangeable site (the E site) undergoes hydrolysis when soluble tubulin adds to the microtubule ends, which creates the nonequilibrium dynamic properties of the microtubules. In its simplest form the assembly may be written as:


where the concentration of polymers, P, depends on the critical concentration of the tubulin subunits for assembly (Sc), the fraction of the proteins that are not participating in the process (f) (for example, because of sequestration by regulatory proteins or denaturation of the tubulin), and the total protein concentration (T) (9). Sc can be determined from the total protein concentration by measuring the polymer content as a function of the total protein concentration at apparent equilibrium. Extrapolation of the total protein concentration to zero polymer content allows determination of the critical concentration. Studies that involve video-enhanced differential interference contrast microscopy and cryo-electron microscopy have provided considerable insight into the nature of growth and shortening of microtubules (10). Accordingly, microtubules, when growing rapidly, display sheet-like extensions at the growing ends, with the eventual closure of the sheets to form the cylindrical microtubule structure. These growing tips are thought to be stabilized by a so-called stabilizing GTP cap (see below). The protofilaments at the ends of rapidly shortening microtubules form tightly curled oligomeric rings, which indicates that GTP hydrolysis creates a strain in the microtubule lattice, and when the cap is lost, the strained and destabilized protofilaments can dissociate rapidly from the microtubule end because of their intrinsic curvature.



Figure 1. Schematic representation of the structure and polymerization of microtubules. Microtubules are cylindrical polymers (diameter, 24 nm), with a distinct molecular polarity conferred by the orientation of tubulin subunits. They exist in a dynamic equilibrium, and their assembly and disassembly depends on the reversible addition and removal of tubulin, which is a heterodimer made up of an alpha and a beta subunit, at the ends of the microtubules.


Dynamics—Mechanistic Aspects

Although the classic model of nucleated helical polymerization accurately describes many aspects of microtubule polymerization, it is now well established that microtubules are not simple equilibrium polymers. Rather, the hydrolysis of GTP to GDP that occurs as tubulin adds to growing microtubule ends creates two unusual nonequilibrium dynamic behaviors, which are known as treadmilling (11, 12) and dynamic instability (13). Treadmilling is the phenomenon of net growth of individual microtubules by the addition of tubulin at one end and net shortening by the loss of tubulin at the other end. Dynamic instability is the stochastic switching between growth and shortening (often called shrinking) phases at the microtubule ends. Although both behaviors are intrinsic properties of microtubules composed solely of tubulin, microtubule dynamics in cells are modulated by a wide variety of microtubule-associated proteins (MAPs) and in an enormous variety of ways (e.g., see Reference 2).



Treadmilling, which is the unidirectional flow or flux of tubulin from plus ends to minus ends (Fig. 2a), was discovered in vitro using single- and double-radiolabeled GTP (3H-GTP and 14C-GTP) incorporation and loss experiments at the microtubule ends by Margolis and Wilson in 1978, while investigating the mechanism of substoichiometric poisoning of microtubule assembly by colchicine (11, 12). Use of double-label and pulse-chase strategies demonstrated that the net uptake and loss of tubulin occurred at opposite ends of the microtubules, whereas the total polymer mass and the lengths of the microtubules remained constant as determined by electron microscopy. These first treadmilling studies were conducted with MAP-rich brain microtubules. Because of the high MAP contact (see below), the treadmilling rates were slow (~ 0.7 μm/h) and dynamic instability was almost completely suppressed. Later, Hotani and Horio provided the first visual proof for treadmilling (14). They decorated the center block of a three-block microtubule with Tetrahymena dynein and found that the length of microtubules at one end of the decorated block decreased and that at the other end increased, which left the length of the center block unchanged. The authors also discovered that in the presence of neural MAPs, dynamic instability was strongly suppressed, which left treadmilling the prevailing dynamic behavior (see Reference 14). Most recently, experiments with microtubules made in the absence of MAPs, but stabilized sufficiently with low concentrations of glycerol to inhibit dynamic instability, demonstrated that the treadmilling rate of MAP-free microtubules in vitro is quite rapid and can approach the rates observed in living cells (15) (see below). This work indicated even more that the treadmilling rate can be increased greatly by increasing the dissociation rate constant for tubulin loss at the minus ends, which is an action that can be accomplished readily by certain MAPs. Treadmilling is believed to be caused by the differences in the individual critical concentrations for tubulin addition at the opposite microtubule ends (15). The idea is that the critical concentration for tubulin assembly at the growing end is lower than at the shortening end, and that at steady state, the overall critical subunit concentration is maintained between the two. For treadmilling to occur, both microtubule ends must be free for tubulin exchange (that is, neither end can be blocked such as occurs at minus ends of microtubules attached to cen- trosomes), and the microtubules must be at or near steady state so that the soluble tubulin level is not so high or so low that both ends grow or shorten. Because treadmilling can occur in the absence of the rapid shortening typical of that observed during dynamic instability, it is reasonable to think that both ends of a treadmilling microtubule retain their stabilizing cap (15).



Figure 2. Treadmilling and dynamic instability of microtubules in vitro. (a) Schematic representation of treadmilling (16). Tubulin heterodimers are added at the plus end of microtubule at arbitrary time 0, they treadmill through the microtubule and are lost from the minus end of the microtubule at time 3. The length of the microtubule is unchanged. Treadmilling is brought about by the different tubulin critical concentrations at the opposite ends. (b). Life-history traces at the plus ends of four individual control microtubules and of microtubules in the presence of 20 n-M griseofulvin, which suppresses the dynamics. The microtubules were assembled from purified bovine brain tubulin, and the changes in length were tracked by using differential interference-contrast microscopy. In the presence of drugs like griseofulvin, dynamics are suppressed (17, p. 4).


Dynamic instability

In 1984, Mitchison and Kirschner (13) discovered dynamic instability in vitro when they observed the coexistence of growing and shrinking populations of microtubules that interconverted infrequently. The coexistence of the two populations of microtubules in a dynamically unstable manner was substantiated by Horio and Hotani by analyzing individual microtubules using dark-field microscopy (3). Dynamic instability thus came to be defined as the stochastic switching between the growing and shortening phases at microtubule ends (Fig. 2b) (16, 17). Dynamic instability in vitro occurs at both microtubule ends, with the dynamics at the plus ends considerably more robust than those as the minus ends (18). In cells, however, dynamic instability has only been observed at plus ends. Minus ends in cells have not been observed to grow; they either remain the same length or they shorten (19).

A minimum of four parameters are now used to define the various features of dynamic instability. These parameters are the growth rate, the shortening rate, and the switching frequencies from growth to shortening and from shortening to growth. The abrupt switching of an end from growth to shortening is referred to as a “catastrophe,” and the switching from shortening to growth is referred to as a “rescue” (18). Additional parameters are used to describe dynamic instability behavior. Specifically, microtubules both in cells and in vitro often do not change length for periods of time. This parameter is called “pause” in cells and “attenuation” in vitro. In both situations, tubulin may be exchanging at the microtubule ends, but the extent of addition or loss may be too low to be detected by video microscopy. An especially useful parameter is termed the “dynamicity” (see Reference 16), which is a measure of the total tubulin exchange per unit time for a microtubule, including periods of attenuation or pause. As examples of the various parameters, Table 1 shows the major dynamic instability parameters for a set of control microtubules in vitro and for microtubules in the presence of the microtubule-targeted drug tasidotin (20).

Hydrolysis of E-site GTP during or shortly after addition of tubulin to the microtubule ends and the gain and loss of a short region of GTP-(or GDP-Pi)-liganded tubulin at the extreme ends of the microtubules that stabilize the microtubule tips are believed responsible for dynamic instability. The tubulin dimer has intrinsic GTPase activity, with a rate that is relatively slow when tubulin is in solution (21). However, hydrolysis is triggered when the β-subunit of an incoming tubulin dimer with bound GTP docks at the end of an exposed α-subunit at the end of the microtubule (22). Evidence in support of the existence of a very short stabilizing GTP cap, perhaps no larger than a single layer of tubulin-GTP (or GDP-Pi), has been obtained in many studies (too numerous to be described here). Studies show that tubulin addition to the microtubule ends and GTP hydrolysis are very closely coupled events (23, 24), and in experiments that use the slowly hydrolysable GTP analog guanylyl-(a, b)-methylene-diphosphonate (GMPCPP), a stable cap is formed from tubulin-GMPCPP subunits (25). The current thinking is that only the tip of the microtubule contains GTP-tubulin (or GDP-Pi) and that the “GTP cap” is required for continued growth to occur. Most of the microtubule core consists of GDP-tubulin, which is believed to be in a strained conformation (1, 10, 26). Thus, when the cap is lost (a catastrophe), the strained GDP-tubulin core is exposed at the ends, which rapidly depolymerize in the form of curved protofilaments (26). The re-establishment of the cap (a rescue) would result in regrowth. The interconversion between these two phases with microtubules composed of pure tubulin (no accessory MAPs) is explained by stochastic loss or by reacquisition of a stabilizing cap by this two-state model, but it is speculated that a closed-tube state, which presumably exists as a structural intermediate between polymerizing ends with sheets and depolymerizing ends with peeling GDP-tubulin oligomers, may represent a structural correlate of a kinetic intermediate in a three-state model (2). A similar model with a growing open state, shrinking state, and a third intermediate closed state has been proposed by Tran et al. (27).


Microtubule Dynamics and its Modulation by Microtubule-Targeted Drugs and Regulatory Proteins

Both dynamic instability and treadmilling occur extensively in all eukaryotic cells. Except for extremely stable microtubules such as those found in organelles such as cilia and flagella, most microtubules are dynamic and display dynamic behaviors that vary enormously in their robustness and type from one cell type to another and even within the cytoplasm of individual cells (2, 18, 28). Dynamic instability and treadmilling (or flux) are extremely rapid during mitosis, and the rapid dynamics are critically important because they are required for distribution of the duplicated chromosomes to the daughter cells in an exquisitely time-sensitive and accurate fashion (29). At the onset of mitosis in animal cells, the dynamics of the microtubules increase many fold and change qualitatively from the dynamics of interphase microtubules. For example, the minus ends of the microtubules tethered at the centrosome during interphase do not seem to grow or shorten. But when the centrosome develops into a mitotic spindle pole, the minus ends become unblocked and dynamically active (29). Also, dynamic instability at the plus ends of the microtubules that grow out from the spindle poles, characterized by frequent switching between growth and shortening states, facilitates microtubule attachment to the kinetochores of the chromosomes (called chromosome capture) and facilitates chromosome alignment at the metaphase plate and their accurate segregation to the daughter cells (29). Robust tubulin flux of kinetochore microtubules from their attachment point at the kinetochore toward their attachment region at the poles, which seems to be treadmilling facilitated by various associated motors and other regulators, creates necessary tension in the spindle and facilitates the accurate and timely segregation of the chromosomes to the daughter cells at anaphase (29). Clearly, whereas spindle microtubules remain tethered at both their plus and minus ends, their ends remain free for rapid flux (see Reference 2). Thus, they must be transiently anchored to other structures near their ends in a fashion that leaves the ends free for subunit loss or gain.

Dynamic microtubules are important not only in dividing cells but also in terminally differentiated cells. For example, they play crucial roles both in the post mitotic development of neurons and in mature neurons such as in the formation of functional neuronal networks and the correct arborization (branching) of dendrites (30). Misregulation of microtubule dynamics, as for example caused by mutations in the neuronal MAP tau, can lead to microtubules whose dynamics fall outside the normally permissible range thus possibly contributing to neurodegeneration in tauopathies such as Alzheimer’s disease and FTDP-17 (Fronto-Temporal Dementia with Parkinsonism associated with Chromosome 17) (see Reference 31) (see below).


Modulation of microtubule dynamics by microtubule-targeted drugs

Here we will focus on how the functions of dynamic microtubules can be modulated powerfully by chemical agents. The fact that microtubule dynamics are indispensable for normal cell function and survival leads naturally to the idea that targeting their dynamics with small molecules is a highly attractive strategy for drug development and chemical biology. This has been especially fruitful in cancer chemotherapy. Several classes of microtubule-targeted drugs are vitally important in the treatment of cancer, which includes the vinca alkaloids and the taxanes. Although high concentrations of these drugs can increase or decrease the mass of assembled microtubules in vitro and in cells, the most sensitive actions of these drugs on microtubules, which occurs at low drug concentrations in the absence of changes in polymer mass, is to suppress their dynamics (16). Despite their opposite effects on microtubule polymerization and their different specific mechanisms of action, most successful chemotherapeutic drugs that act on microtubules share the common property of suppressing spindle microtubule dynamics, which leads to inhibition or slowing of cell cycle progression at prometaphase of mitosis and at the transition from metaphase to anaphase (32). In sensitive tumor cells, mitotic arrest is followed by apoptosis. The mechanism that underlies the relationship between disruption of spindle dynamics and induction of apoptosis is yet to be fully explored, although evidence that diffusible factors maybe released as the result of changes in microtubule polymerization is consistent with the hypothesized role of microtubules in sequestering signals (33). In fact, several successful microtubule-targeting drugs are known to promote apoptosis in tumor cells (34).

Microtubule interfering drugs act by binding to various sites on the tubulin dimer and at different positions within the microtubule. Although other categories clearly exist, currently most drugs are classified into three major categories based on their respective tubulin binding domains: which include the Vinca alkaloid domain, the colchicine domain, and the paclitaxel domain. These may be some of the same regions of microtubule surfaces used by natural regulators of dynamics in cells and, thus, the drugs can be thought of as possible mimics of microtubule regulatory proteins (35). Vincristine and vinblastine have long been used for the treatment of hematological cancers. Vinca alkaloids currently used for treatment of cancer include two natural products: vincristine, and vinblastine, and several novel semi-synthetic drugs, vindesine, vinorelbine and vinflunine. At low concentrations, vinca alkaloids suppress both dynamic instability and treadmilling, apparently by binding to microtubule ends. The superior antitumor efficacy and reduced toxicity of vinflunine (36) over vinblastine may be attributed to its less powerful inhibitory effects on microtubule dynamics. Defective checkpoints in certain cancer cells may make them more susceptible to the less powerful inhibitory effects of vinflunine than normal cells (36). Drugs such as vinflunine, various derivatives of the dolastatins including tasidotin (20) (Table 1), cryptophycin analogs (37), and halichondrin B analogs such as eribulin (E7389) (38) comprise a series of chemically distinct compounds that bind in the vicinity of the Vinca binding domain and are under various stages of development for cancer treatment. The microtubule seems to be exquisitely sensitive to the action of these drugs as the binding of only a few drug molecules along the microtubule surface or at its ends is sufficient to suppress microtubule dynamics (see Reference 16).

Colchicine and compounds that bind in the vicinity of the colchicine-binding domain of tubulin comprise another class of drugs with potential for treatment of cancer. Colchicine binds to tubulin at α:β dimer interface, and acts by being incorporated with low stoichiometry at the ends of the microtubules as a tubulin-colchicine complex (39). Although colchicine has antitumor properties, its therapeutic use is hampered by its high toxicity. Drugs that bind to tubulin at or near the colchicine site that are in clinical trials include 2-methoxyestradiol and combretastatin A4 phosphate. 2-methoxyestradiol induces mitotic arrest by suppression of microtubule dynamics (40), whereas the vascular targeting agent combretastatin A4 phosphate acts by destabilizing microtubules (41).

Paclitaxel and docetaxel are among the most successful microtubule-targeted drugs currently used to treat solid tumors, which include ovarian, breast, head and neck, lung, and prostate (42). The binding site for the taxanes is on the β-tubulin and is located on the inside surface of the microtubule (43). Binding of only a few molecules of paclitaxel to tubulin in microtubules strongly suppresses dynamic instability at microtubule plus ends with only a marginal increase in microtubule polymer mass (44). Other promising anticancer compounds believed to act at the taxane binding sites include the epothilones (45), discodermolide (46), eleutherobin, and several novel taxanes (47). Paclitaxel may find a role in the treatment of neurodegenerative diseases. Specifically, it improved axonal function and ameliorated neurological problems in mice that carry a defective human tau gene (48). Interestingly, some evidence indicates that paclitaxel and tau may share the same binding site on the microtubule surface (49), and the effects of tau on microtubule dynamics are rather similar to those of paclitaxel (31).


Table 1. Effects of 5 μM tasidotin on selected dynamic instability parameters at plus ends of microtubules at steady state in vitro (20)





















1.7 ± 0.8

28.4 ± 2.0

0.5 ± 0.01

1.8 ± 0.2



1.9 ± 0.1

9.0 ± 0.7

0.2 ± 0.01

1.1 ± 0.1



Regulation of microtubule dynamics by cellular MAPs

A plethora of proteins regulate microtubule dynamics in cells. All these regulators are potential targets for chemical biology. As indicated earlier, evidence indicates that the drug molecules may mimic the effects of natural regulators of dynamics, perhaps by binding to the microtubules at similar sites or regions of tubulin (35). Cellular proteins that regulate microtubule dynamics have traditionally been classified into two groups: microtubule-stabilizing proteins and microtubule-destabilizing proteins. A third recently described group of proteins known as + TIPs, which track the plus ends of growing microtubules in cells, also are thought to regulate microtubule dynamics (28).


Regulation by stabilizing proteins

Several MAPs have been known for to promote tubulin assembly and to stabilize microtubules. Members of this family include the neuronal proteins tau and MAP2, which are present in axons and dendrites, respectively, and MAP4, which is found in all non-neuronal vertebrate cells (50). This group of structural MAPs also includes MAP1A and MAP1B, which are found mainly in axons and dendrites (51, 52). Regulation by these MAPs is complex because their ability to regulate polymerization and dynamics is in turn regulated by phosphorylation (53). Currently, tau is attracting considerable attention because of its involvement in various neurodegenerative diseases and because it may be a target possible treatment of Alzheimer’s disease (31,54-56). Tau is a complex family of MAPs found specifically in neurons that strongly promotes microtubule polymerization and stabilizes microtubules. Although only a single tau gene exists, six developmentally regulated tau isoforms are produced in human brain because of alternative splicing of the single tau gene. Tau is also the target of multiple kinases that can phosphorylate it at a great many sites, which produces many more isoforms. The various tau isoforms differentially modulate dynamic instability (reviewed in Reference 31). For example, an adult form of tau with 4 microtubule binding repeats (called 4 R tau) strongly suppresses the shortening rate at plus ends, whereas a fetal form of tau with only 3 repeats (3 R tau) does not (55). In the neurodegenerative disease FTDP-17, mutations that result in altered mRNA splicing change the crucial expression ratio of the 3 R and 4 R tau isoforms (56). Altered expression of normal tau isoforms could result in misregulation of microtubule dynamic in axons and thus contribute to neurodegenerative disease.


Regulation by destabilizing proteins

Stathmin/Op18 (oncoprotein18) and certain members of the kinesin-related motor proteins are among the major classes of proteins that cause microtubule destabilization. Stathmin is a ubiquitous microtubule-destabilizing protein that is believed to play an important role in linking cell signaling to the regulation of microtubule dynamics. It is known to sequester free tubulin and therefore to impede microtubule formation (57). Clearly, such an action can affect microtubule dynamics. But like the action on microtubules of many drugs, the effects of stathmin on tubulin and microtubules are complex. Specifically, relatively low concentrations of stathmin increase the steady-state catastrophe frequency by a direct action on microtubules, with the catastrophe-promoting activity being considerably stronger at the minus ends than at the plus ends (58). Stathmin also greatly increases the microtubule treadmilling rate. These data indicate that stathmin may be an important regulator of minus-end dynamics, as for example, by increasing depolymerization at microtubule minus ends at spindle poles during mitosis thereby increasing the plus to minus end flux rate (58). Other destabilizing proteins include microtubule severing proteins such as katanin (59) and the kinesin-related motor protein, XKCM1 (60).


Plus end tracking proteins

Finally, we want to mention briefly a group of proteins known as + TIPs or plus-end tracking proteins (28). This group of proteins is composed of microtubule motor complex components, signal transduction molecules, and molecular adaptors. These proteins can recognize and associate with growing microtubule plus ends and include CLIP-170 (cytoplasmic linker protein), which is an endosome-microtubule linker protein that was the first + TIP identified; members of the family EB1, EB2, and EB3 (end-binding proteins) that bind to APC (adenomatous polyposis coli, a tumor suppressor protein); the dynein/dynactin microtubule motor complex, in particular the 150glued subunit of dynactin; and several other proteins such as CLASP1 (CLIP-associated protein) and LIS1 (28, 61). EB1 enhances microtubule polymerization by increasing rescues and preventing catastrophes (62). Using dominant negative constructs, it was shown that in the absence of CLIPs, the microtubule rescue frequency was reduced, which suggests a mechanism that involves CLIPs by which microtubule plus ends may be concentrated near the cell margin (63). Although many functions of the + TIPs are not yet understood, targeting their association with the growing tips of microtubules could be an area for future development through chemical biology.



Treadmilling and dynamic instability—two intrinsic dynamic properties of microtubules—are critical for mitosis and many other cellular functions that involve dynamic microtubules. Because the dynamics of microtubules and their tight regulation by a host of MAPs play crucial roles in so many cell functions, it is reasonable to think that modulating their dynamics in specific cell functions by targeting the microtubules themselves or by targeting the regulatory proteins through chemical biology will remain an attractive area of research for many years to come.



We acknowledge the support of USPHS grant NS13560, which supported the authors.



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Further Reading

Avila J. Microtubule Proteins. 1989. CRC Press, Boca Raton, FL. This book covers various aspects of microtubule and microtubule-associated proteins. In addition, detailed descriptions of the relationship between microtubule structure and functions, microtubule proteins, it elaborates microtubule dynamics, and microtubule poisons.

Hyams JS, Lloyd CW. Microtubules. 1993. Wiley-Liss Inc., New York. Advances in microtubule biology are described in detail. In depth coverage of microtubule dynamics and functions in cells is included.

Soifer D. Dynamic Aspects of Microtubule Biology. 1986. New York Academy of Sciences, New York. Dynamic Aspects of Microtubule Biology is a compilation of works describing the emerging trends and early concepts about microtubule dynamics. The book features some of the seminal works in this field.

Wilson L, Jordan MA. Microtubule dynamics: taking aim at a moving target. Chem. Biol. 1995; 2:569-573.


See Also

Microtubules: Topics in Chemical Biology

Cytoskeleton and Cellular Motility: Topics in Chemical Biology

Actin Cytoskeletal Dynamics

Microtubule-Based Motility

Natural Product Inhibitors to Study Biological Function