Stathmin

Stathmin 1/oncoprotein 18, also known as STMN1, is a highly conserved 17kDa protein. Its function as an important regulatory protein of microtubule dynamics has been well characterized. ^[1] Eukaryotic microtubules are one of three major components of the cell’s cytoskeleton. They are highly dynamic structures that continuously alternate between assembly and disassembly. Stathmin performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cell’s needs. Microtubules are cylindrical polymers of α,β-tubulin. Their assembly is in part determined by the concentration of free tubulin in the cytoplasm. ^[2]

At low concentrations of free tubulin, the growth rate at the microtubule ends is slowed and results in an increased rate of depolymerization (disassembly). ^{[3] [1]}

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Function

Stathmin interacts with two molecules of dimeric α,β-tubulin to form a tight ternary complex called the T2S complex. ^[1] One mole of stathmin binds to two moles of tubulin dimers through the stathmin-like domain (SLD). ^[3] When stathmin sequesters tubulin into the T2S complex, tubulin becomes nonpolymerizable. Without tubulin polymerization, there is no microtubule assembly. Through this mechanism, stathmin promotes microtubule disassembly without acting directly on the microtubule ends. ^[1]

The rate of microtubule assembly is an important aspect of cell growth therefore associating regulation of stathmin with cell cycle progress. Regulation of stathmin is cell cycle dependent and controlled by the cell’s protein kinases in response to specific cell signals. ^{[3] [1]} Phosphorylation at four serine residues on stathmin named Ser16, Ser25, Ser38 and Ser63 causes weakened stathmin-tubulin binding. Stathmin phosphorylation increases the concentration of tubulin available in the cytoplasm for microtubule assembly. For cells to assemble the mitotic spindle necessary for initiation of the mitotic phase of the cell cycle, stathmin phosphorylation must occur. Without microtuble growth and assembly, the mitotic spindle cannot form, and the cell cycle is arrested. At cytokinesis, the last phase of the cell cycle, rapid dephosphorylation of stathmin occurs to block the cell from entering back into the cell cycle until it is ready. ^[3]

Oncoprotein Characterization

Stathmin’s role in regulation of the cell cycle causes it to be an oncoprotein named oncoprotein 18 (op18). As op18, stathmin can cause uncontrolled cell proliferation when mutated and not functioning properly. If stathmin is unable to bind to tubulin, it allows for constant microtubule assembly and therefore constant mitotic spindle assembly. With no regulation of the mitotic spindle, the cell cycle is capable of cycling uncontrollably resulting in the unregulated cell growth characteristic of cancer cells. ^[3]

References

Further reading