Mitotic Centromere-Associated Kinesin (MCAK/KIF2C) Regulates Cell Migration and Invasion by Modulating Microtubule Dynamics and Focal Adhesion Turnover

Abstract

The microtubule (MT) cytoskeleton is crucial for cell motility and migration by regulating multiple cellular activities such as transport and endocytosis of key components of focal adhesions (FA). The kinesin-13 family is important in the regulation of MT dynamics and the best characterized member of this family is the mitotic centromere-associated kinesin (MCAK/KIF2C). Interestingly, its overexpression has been reported to be related to increased metastasis in various tumor entities. Moreover, MCAK is involved in the migration and invasion behavior of various cell types. However, the precise molecular mechanisms were not completely clarified. To address these issues, we generated CRISPR/dCas9 HeLa and retinal pigment epithelium (RPE) cell lines overexpressing or downregulating MCAK. Both up- or downregulation of MCAK led to reduced cell motility and poor migration in malignant as well as benign cells. Specifically, it’s up- or downregulation impaired FA protein composition and phosphorylation status, interfered with a proper spindle and chromosome segregation, disturbed the assembly and disassembly rate of FA, delayed cell adhesion, and compromised the plus-tip dynamics of MTs. In conclusion, our data suggest MCAK act as an important regulator for cell motility and migration by affecting the actin-MT cytoskeleton dynamics and the FA turnover, providing molecular mechanisms by which deregulated MCAK could promote malignant progression and metastasis of tumor cells.

Large-Scale Transcriptome Data Analysis Identifies KIF2C as a Potential Therapeutic Target Associated With Immune Infiltration in Prostate Cancer

“…According to An et al (20), KIF2C increased cancer growth and was linked to tumor immune cell infiltration in endometrial cancer. According to Ha et al (21), KIF2C promotes tumor cell motility and invasion. Furthermore, Zhu et al suggested that KIF2C is a new player in the DNA damage response (22).…”

Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis

“…Although at first glance this may appear paradoxical in light of the tightly regulated DCLK1/MT interactions, it could suggest that affecting the ratio of DCLK1 bound to MTs interferes with proper MT dynamics, which underpins mitosis, cell signaling, trafficking migration and other cancer-relevant activities. Indeed, such a bimodal mechanism on MT dynamics has been demonstrated for MT depolymerase mitotic centromere-associated kinesin (MCAK) [ 123 ]. However, there may be DCLK1-dependent tumor-promoting mechanisms independent of its MT association.…”

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer

“…Overexpression of KIF2C could promote cancer cell proliferation, migration, invasion, and metastasis by increasing the mTORC1 signaling transduction [ 21 ]. Moon et al reported that KIF2C was able to control cancer cell migration and invasion through modulating MT dynamics and focal adhesion turnover [ 27 ]. Several previous studies have shown that KIF2C and other kinesins were overexpressed in breast cancer and associated with worse prognosis [ 29 – 33 ].…”