title: A novel role for Plk4 in regulating cell spreading and motility.
abstract: Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4(+/-) murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4(+/-) MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: C O
authors.initials: CO
authors.lastname: Rosario
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Surgery, University of Toronto, Toronto, ON, Canada [3] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Kazazian
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Surgery, University of Toronto, Toronto, ON, Canada [3] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: F S W
authors.initials: FS
authors.lastname: Zih
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: O
authors.initials: O
authors.lastname: Brashavitskaya
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Haffani
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: R S Z
authors.initials: RS
authors.lastname: Xu
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: George
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada [3] Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: J W
authors.initials: JW
authors.lastname: Dennis
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada [3] Department of Surgery, University of Toronto, Toronto, ON, Canada [4] Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Swallow
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D004622:Embryo, Mammalian; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases