title: PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2.
abstract: Components of the evolutionarily conserved developmental planar cell polarity (PCP) pathway were recently described to play a prominent role in cancer cell dissemination. However, the molecular mechanisms by which PCP molecules drive the spread of cancer cells remain largely unknown. PRICKLE1 encodes a PCP protein bound to the promigratory serine/threonine kinase MINK1. We identify RICTOR, a member of the mTORC2 complex, as a PRICKLE1-binding partner and show that the integrity of the PRICKLE1-MINK1-RICTOR complex is required for activation of AKT, regulation of focal adhesions, and cancer cell migration. Disruption of the PRICKLE1-RICTOR interaction results in a strong impairment of breast cancer cell dissemination in xenograft assays. Finally, we show that upregulation of PRICKLE1 in basal breast cancers, a subtype characterized by high metastatic potential, is associated with poor metastasis-free survival.
authors.affiliation: Inserm, U1068, CRCM, Cell Polarity, Cell Signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France; Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France.
authors.forename: Avais M
authors.initials: AM
authors.lastname: Daulat
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, Molecular Oncology "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Inserm, U1068, CRCM, Cell Polarity, Cell Signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France; Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Audebert
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, Leuko/Stromal Interactions, Marseille 13009, France.
authors.forename: Arnauld
authors.initials: A
authors.lastname: Sergé
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, Molecular Oncology "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, TrGET Platform, Marseille 13009, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, TrGET Platform, Marseille 13009, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.affiliation: Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France; Inserm, U1068, CRCM, Molecular Oncology "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S3M2, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, ON M5S1A8, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Angers
authors.affiliation: Inserm, U1068, CRCM, Cell Polarity, Cell Signalling and Cancer "Equipe labellisée Ligue Contre le Cancer", Marseille 13009, France; Institut Paoli-Calmettes, Marseille 13009, France; Aix-Marseille Université, UM 105, Marseille 13284, France; CNRS, UMR7258, CRCM, Marseille 13009, France. Electronic address: jean-paul.borg@inserm.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D060588:LIM Domain Proteins / Q000737:chemistry / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011379:Prognosis; D011485:Protein Binding; D000072417:Protein Domains; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D060588:LIM Domain Proteins; D046912:Multiprotein Complexes; C515173:PRICKLE1 protein, human; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D025521:Tumor Suppressor Proteins; C497353:MINK1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: MINK1; PRICKLE1; cancer cell migration; mTORC2