PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2

Avais M Daulat; François Bertucci; Stéphane Audebert; Arnauld Sergé; Pascal Finetti; Emmanuelle Josselin; Rémy Castellano; Daniel Birnbaum; Stéphane Angers; Jean-Paul Borg

doi:10.1016/j.devcel.2016.04.011

PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2

Dev Cell. 2016 May 23;37(4):311-325. doi: 10.1016/j.devcel.2016.04.011. Epub 2016 May 12.

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 27184734
DOI: 10.1016/j.devcel.2016.04.011

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.

Keywords: MINK1; PRICKLE1; cancer cell migration; mTORC2.

MeSH terms

Breast Neoplasms / pathology*
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Movement
Cell Proliferation
Female
Focal Adhesions / metabolism
Genes, Dominant
Humans
LIM Domain Proteins / chemistry
LIM Domain Proteins / metabolism*
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes / metabolism*
Neoplasm Metastasis
Phosphorylation
Prognosis
Protein Binding
Protein Domains
Protein Interaction Mapping
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rapamycin-Insensitive Companion of mTOR Protein
TOR Serine-Threonine Kinases / metabolism*
Tumor Suppressor Proteins / chemistry
Tumor Suppressor Proteins / metabolism*
Up-Regulation

Substances

Carrier Proteins
LIM Domain Proteins
Multiprotein Complexes
PRICKLE1 protein, human
RICTOR protein, human
Rapamycin-Insensitive Companion of mTOR Protein
Tumor Suppressor Proteins
MINK1 protein, human
Mechanistic Target of Rapamycin Complex 2
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases