title: Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells.
abstract: Mitotic centromere-associated kinesin (MCAK) is the best characterized member of the kinesin-13 family and plays important roles in microtubule dynamics during mitosis. Its activity and subcellular localization is tightly regulated by an orchestra of mitotic kinases, such as Aurora B. It is well known that serine 196 of MCAK is the major phosphorylation site of Aurora B in Xenopus leavis extracts and that this phosphorylation regulates its catalytic activity and subcellular localization. In the current study, we have addressed the conserved phosphorylation site serine 192 in human MCAK to characterize its function in more depth in human cancer cells. Our data confirm that S192 is the major phosphorylation site of Aurora B in human MCAK and that this phosphorylation has crucial roles in regulating its catalytic activity and localization at the kinetochore/centromere region in mitosis. Interfering with this phosphorylation leads to a delayed progression through prometa- and metaphase associated with mitotic defects in chromosome alignment and segregation. We show further that MCAK is involved in directional migration and invasion of tumor cells, and interestingly, interference with the S192 phosphorylation affects this capability of MCAK. These data provide the first molecular explanation for clinical observation, where an overexpression of MCAK was associated with lymphatic invasion and lymph node metastasis in gastric and colorectal cancer patients.
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritter
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Mourad
authors.initials: M
authors.lastname: Sanhaji
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Friemel
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roth
authors.affiliation: b Department of Pediatric Surgery and Pediatric Urology ; School of Medicine; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rolle
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Louwen
authors.affiliation: a Department of Gynecology and Obstetrics ; JW Goethe-University ; Frankfurt , Germany.
authors.forename: Juping
authors.initials: J
authors.lastname: Yuan
mesh_terms: D064107:Aurora Kinase B / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000737:chemistry* / Q000502:physiology; D008938:Mitosis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
chemical_list: C091489:KIF2C protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D016547:Kinesins
keywords: Aurora B; MCAK phosphorylation; cell motility; microtubule dynamics; mitotic defect