Spatial regulation of MCAK promotes cell polarization and focal adhesion turnover to drive robust cell migration.

Hailing Zong, Mark Hazelbaker, Christina Moe, Stephanie C Ems-McClung, Ke Hu, Claire E Walczak

Molecular biology of the cell 2021 Apr 01

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The asymmetric distribution of microtubule (MT) dynamics in migrating cells is important for cell polarization, yet the underlying regulatory mechanisms remain underexplored. Here, we addressed this question by studying the role of the MT depolymerase, MCAK (mitotic centromere-associated kinesin), in the highly persistent migration of RPE-1 cells. MCAK knockdown leads to slowed migration and poor directional movement. Fixed and live cell imaging revealed that MCAK knockdown results in excessive membrane ruffling as well as defects in cell polarization and the maintenance of a major protrusive front. Additionally, loss of MCAK increases the lifetime of focal adhesions by decreasing their disassembly rate. These functions correlate with a spatial distribution of MCAK activity, wherein activity is higher in the trailing edge of cells compared with the leading edge. Overexpression of Rac1 has a dominant effect over MCAK activity, placing it downstream of or in a parallel pathway to MCAK function in migration. Together, our data support a model in which the polarized distribution of MCAK activity and subsequent differential regulation of MT dynamics contribute to cell polarity, centrosome positioning, and focal adhesion dynamics, which all help facilitate robust directional migration.

Citation

Hailing Zong, Mark Hazelbaker, Christina Moe, Stephanie C Ems-McClung, Ke Hu, Claire E Walczak. Spatial regulation of MCAK promotes cell polarization and focal adhesion turnover to drive robust cell migration. Molecular biology of the cell. 2021 Apr 01;32(7):590-604