title: PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position.
abstract: Disruption of epithelial architecture is a fundamental event during epithelial tumorigenesis. We show that the expression of the cancer-promoting phosphatase PRL-3 (PTP4A3), which is overexpressed in several epithelial cancers, in polarized epithelial MDCK and Caco2 cells leads to invasion and the formation of multiple ectopic, fully polarized lumens in cysts. Both processes disrupt epithelial architecture and are hallmarks of cancer. The pathological relevance of these findings is supported by the knockdown of endogenous PRL-3 in MCF-7 breast cancer cells grown in three-dimensional branched structures, showing the rescue from multiple-lumen- to single-lumen-containing branch ends. Mechanistically, it has been previously shown that ectopic lumens can arise from midbodies that have been mislocalized through the loss of mitotic spindle orientation or through the loss of asymmetric abscission. Here, we show that PRL-3 triggers ectopic lumen formation through midbody mispositioning without altering the spindle orientation or asymmetric abscission, instead, PRL-3 accelerates cytokinesis, suggesting that this process is an alternative new mechanism for ectopic lumen formation in MDCK cysts. The disruption of epithelial architecture by PRL-3 revealed here is a newly recognized mechanism for PRL-3-promoted cancer progression.
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
authors.forename: Pablo
authors.identifier: 0000-0001-8340-100X
authors.initials: P
authors.lastname: Luján
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Varsano
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany.
authors.forename: Teresa
authors.identifier: 0000-0003-0843-528X
authors.initials: T
authors.lastname: Rubio
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg 69117, Germany.
authors.forename: Marco L
authors.identifier: 0000-0003-2853-9748
authors.initials: ML
authors.lastname: Hennrich
authors.affiliation: Heidelberg University Biochemistry Center, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Sachsenheimer
authors.affiliation: Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28049, Spain.
authors.forename: Manuel
authors.identifier: 0000-0002-2564-4430
authors.initials: M
authors.lastname: Gálvez-Santisteban
authors.affiliation: Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28049, Spain.
authors.forename: Fernando
authors.identifier: 0000-0002-2564-4430
authors.initials: F
authors.lastname: Martín-Belmonte
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg 69117, Germany.
authors.forename: Anne-Claude
authors.identifier: 0000-0003-4917-2340
authors.initials: AC
authors.lastname: Gavin
authors.affiliation: Heidelberg University Biochemistry Center, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Brügger
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg 69117, Germany koehn@embl.de.
authors.forename: Maja
authors.identifier: 0000-0001-8142-3504
authors.initials: M
authors.lastname: Köhn
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D016764:Cell Polarity; D048430:Cell Shape; D048749:Cytokinesis; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D008938:Mitosis; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: Cancer; Cell polarity; Epithelia; Midbody; PRL-3; PTP4A3