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Functional characterization of MCAK/Kif2C cancer mutations using high-throughput microscopic analysis
Mike Wagenbach1, Juan Jesus Vicente1, Yulia Ovechkina1
1Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195.
Molecular Biology of the Cell
|November 21, 2019
Summary
Mutations in the microtubule-depolymerizing kinesin MCAK/Kif2C can impair its function and promote chromosome instability. Its activity is finely tuned in cells to prevent errors in chromosome segregation.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Microtubule dynamics are crucial for cell division.
- MCAK/Kif2C is a key motor protein regulating microtubule depolymerization.
- Dysregulation of MCAK/Kif2C is implicated in cancer development.
Purpose of the Study:
- To quantify the microtubule (MT)-depolymerizing activity of MCAK/Kif2C.
- To assess the impact of motor domain mutations on MCAK/Kif2C function.
- To investigate the role of MCAK/Kif2C in chromosome instability.
Main Methods:
- Expression of MCAK/Kif2C in cultured cells.
- Measurement of tubulin fluorescence levels.
- Utilizing CellProfiler for high-throughput imaging and analysis.
- Analysis of MCAK/Kif2C mutations from the cBioPortal cancer database.
- Employing CRISPR technology for targeted gene editing.
Main Results:
- Many mutations affecting transport kinesins also impair MCAK/Kif2C depolymerizing activity.
- A significant proportion of cancer-associated MCAK/Kif2C mutations adversely affect motor function.
- A specific hot-spot mutation increased chromosome instability in a wild-type background.
- Elevated levels of wild-type MCAK/Kif2C also increased chromosome instability.
Conclusions:
- MCAK/Kif2C's depolymerizing activity is sensitive to specific motor domain mutations, including those found in cancer.
- Certain MCAK/Kif2C mutations can promote chromosome instability, potentially driving tumor evolution.
- Endogenous MCAK/Kif2C levels are precisely regulated to maintain genomic stability, suggesting a critical threshold for its function.
