Regulation of Microtubule Dynamics

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Pathway Description:

Microtubules are required for the establishment of cell polarity, polarized migration of cells, intracellular vesicle transport, and chromosomal segregation in mitosis. Microtubules (MTs) are non-equilibrium polymers of α/β-tubulin heterodimers, in which GTP hydrolysis on the β-tubulin subunit occurs following assembly. Most microtubules are nucleated from organizing centers. The most prevalent microtubule behavior is dynamic instability, a process of slow plus end growth coupled with rapid depolymerization (“catastrophe”) and subsequent rescue. Although microtubule minus ends show dynamic instability, albeit at a lower rate than the plus ends, the minus ends are usually capped and anchored at MT organizing centers and thus often do not participate in microtubule dynamics. Because of their role in mitosis, microtubules have been targets of chemotherapy in cancer.

Maintaining a balance between dynamically unstable and stable microtubules is regulated in large part by proteins that bind either tubulin dimers or assembled microtubules. Proteins that bind tubulin dimers include stathmin (aka Op18), which sequesters tubulin and enhances MT dynamics by increasing catastrophe frequency, and collapsin response mediator protein (CRMP2), which increases MT growth rate by promoting addition of tubulin dimers onto microtubule plus ends. Stathmin prevents sequestered tubulin from being incorporated into MTs, but it also enhances catastrophes, probably through its ability to bind protofilaments at each end of a MT. Other proteins that associate with assembled MTs include those that bundle MTs (e.g. MAP1c), those that stabilize MTs (e.g. tau), and those that maintain MTs in a dynamic state (MAP1b). A major signaling pathway that regulates MT dynamics involves GSK-3β, a kinase typically active under basal growth conditions but locally inactive in response to signals that enhance MT growth and dynamics. CRMP2 and MAP1b are substrates for GSK-3β.

In addition to the above factors, many MT motor proteins, and even non-motor proteins, aid in the dynamics of MTs. Proteins such as Xenopus microtubule associated protein (MAP)215 (XMAP215), promote MT assembly through binding to tubulin dimer to facilitate its incorporation in the growing plus end. This protein can also enhance depolymerization if tubulin dimer levels are low. XMAP215 also may compete with some of the MT plus end binding proteins (+TIPS), of which the end binding protein EB1 appears to be the master organizer. Some +TIPS require kinesin motors to localize them to the MT plus ends; however the +TIPS move with the growing plus end in the absence of MT motors. Complexes between the adenomateous polyposis coli (APC) protein and plus end binding proteins stabilize MTs by increasing the duration of the MT elongation phase. Interactions between APC and other +TIPS can also result in the delivery of associated cargo proteins to the cell periphery. MT instability is promoted by several nonmotile kinesins from the kinesin-13 family. The mitotic centromere associated kinesin, MCAK, one of the most studied kinesin-13 family proteins, binds both plus and minus MT ends in vitro and has the highest affinity for the curved protofilaments resembling those from a shrinking MT. The binding of MCAK to a MT end is thought to accelerate the transition to catastrophe by weakening the lateral interactions between the protofilaments. MCAK is phospho-regulated by Aurora B kinase during mitosis and activated by the inner centromere Kin1-stimulator (ICIS).

Tubulin undergoes several posttranslational modifications such as acetylation, poly-glutamylation, and poly-glycylation which have been shown to alter the association with certain MT motors as well as other proteins that can affect MT stability and dynamics.

Selected Reviews:

• Etienne-Manneville S (2010) From signaling pathways to microtubule dynamics: the key players. Curr. Opin. Cell Biol. 22(1), 104–11.
• Hoogenraad CC, Bradke F (2009) Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends Cell Biol. 19(12), 669–76.
• Kawauchi T, Hoshino M (2008) Molecular pathways regulating cytoskeletal organization and morphological changes in migrating neurons. Dev. Neurosci. 30(1-3), 36–46.
• van der Vaart B, Akhmanova A, Straube A (2009) Regulation of microtubule dynamic instability. Biochem. Soc. Trans. 37(Pt 5), 1007–13.