Cell Signaling Technology

Regulation of Microtubule Dynamics

Regulation of Microtubule Dynamics

Pathway Description:

Microtubules are required for the establishment of cell polarity, polarized migration of cells, intracellular vesicle transport and chromosomal segregation in mitosis. Microtubules (MT) 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”) subsequent rescue. Microtubule minus ends are capped and do not participate in microtubule dynamics, except when treadmilling occurs at specific times in mitosis. 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 the stathmins, which sequester tubulin and enhance 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. Proteins that associate with assembled microtubules include those that bundle microtubules (e.g. MAP1c), those that stabilize microtubules (e.g. tau), and those that maintain microtubules 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.

The adenomateous polyposis coli (APC) protein associates with MT plus end binding proteins (+TIPS), some of which require kinesin motors to localize them to the microtubule plus ends. Complexes between APC and plus end binding proteins stabilize microtubules by increasing the duration of the MT elongation phase. Interactions between APC and +TIPS can also result in the delivery of cargo proteins to the cell periphery. Transported proteins include polarity complex proteins, Rho GTPase activating proteins, and non-receptor tyrosine kinases. Some proteins delivered by microtubule plus ends locally modulate actin filament dynamics, which is important for directed cell migration. Microtubules that reach the actin cortex or cell membrane are often captured and stabilized by actin- or membrane-binding proteins that also bind APC.

Selected Reviews:

CST would like to thank Prof. Gary M. Bokoch, Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, California, and Prof. James R. Bamburg Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, for creating this diagram.

created September 2008

Reference