A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

Alejandro Conde-Perez; Gwendoline Gros; Christine Longvert; Malin Pedersen; Valérie Petit; Zackie Aktary; Amaya Viros; Franck Gesbert; Véronique Delmas; Florian Rambow; Boris C. Bastian; Andrew D. Campbell; Sophie Colombo; Isabel Puig; Alfonso Bellacosa; Owen Sansom; Richard Marais; Leon C.L.T. Van Kempen; Lionel Larue

doi:10.1038/ncomms9093

A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

Alejandro Conde-Perez, Gwendoline Gros, Christine Longvert, Malin Pedersen, Valérie Petit, Zackie Aktary, Amaya Viros, Franck Gesbert, Véronique Delmas, Florian Rambow, Boris C. Bastian, Andrew D. Campbell, Sophie Colombo, Isabel Puig, Alfonso Bellacosa, Owen Sansom, Richard Marais, Leon C.L.T. Van Kempen, Lionel Larue

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRAS Q61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β-catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

Original language	English
Article number	8093
Pages (from-to)	8093
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9093
State	Published - Aug 26 2015

Keywords

Animals
Blotting, Western
Cadherins/metabolism
Caveolin 1/genetics
Cell Line, Tumor
Feedback, Physiological
GTP Phosphohydrolases/genetics
Glycogen Synthase Kinase 3 beta
Glycogen Synthase Kinase 3/metabolism
Humans
Immunohistochemistry
Melanocytes/metabolism
Melanoma/genetics
Membrane Proteins/genetics
Mice
Mice, Transgenic
MicroRNAs
Microscopy, Fluorescence
PTEN Phosphohydrolase/genetics
Phosphatidylinositol 3-Kinases/metabolism
Prognosis
Proto-Oncogene Proteins c-akt/metabolism
Skin Neoplasms/genetics
Transcriptional Activation/genetics
beta Catenin/metabolism

Access to Document

10.1038/ncomms9093

Cite this

Conde-Perez, A., Gros, G., Longvert, C., Pedersen, M., Petit, V., Aktary, Z., Viros, A., Gesbert, F., Delmas, V., Rambow, F., Bastian, B. C., Campbell, A. D., Colombo, S., Puig, I., Bellacosa, A., Sansom, O., Marais, R., Van Kempen, L. C. L. T., & Larue, L. (2015). A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity. Nature Communications, 6, 8093. Article 8093. https://doi.org/10.1038/ncomms9093

@article{d89d83ff007a479283e36d58b80a4caf,

title = "A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity",

abstract = "Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRAS Q61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β-catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.",

keywords = "Animals, Blotting, Western, Cadherins/metabolism, Caveolin 1/genetics, Cell Line, Tumor, Feedback, Physiological, GTP Phosphohydrolases/genetics, Glycogen Synthase Kinase 3 beta, Glycogen Synthase Kinase 3/metabolism, Humans, Immunohistochemistry, Melanocytes/metabolism, Melanoma/genetics, Membrane Proteins/genetics, Mice, Mice, Transgenic, MicroRNAs, Microscopy, Fluorescence, PTEN Phosphohydrolase/genetics, Phosphatidylinositol 3-Kinases/metabolism, Prognosis, Proto-Oncogene Proteins c-akt/metabolism, Skin Neoplasms/genetics, Transcriptional Activation/genetics, beta Catenin/metabolism",

author = "Alejandro Conde-Perez and Gwendoline Gros and Christine Longvert and Malin Pedersen and Val{\'e}rie Petit and Zackie Aktary and Amaya Viros and Franck Gesbert and V{\'e}ronique Delmas and Florian Rambow and Bastian, {Boris C.} and Campbell, {Andrew D.} and Sophie Colombo and Isabel Puig and Alfonso Bellacosa and Owen Sansom and Richard Marais and {Van Kempen}, {Leon C.L.T.} and Lionel Larue",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = aug,

day = "26",

doi = "10.1038/ncomms9093",

language = "English",

volume = "6",

pages = "8093",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Conde-Perez, A, Gros, G, Longvert, C, Pedersen, M, Petit, V, Aktary, Z, Viros, A, Gesbert, F, Delmas, V, Rambow, F, Bastian, BC, Campbell, AD, Colombo, S, Puig, I, Bellacosa, A, Sansom, O, Marais, R, Van Kempen, LCLT & Larue, L 2015, 'A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity', Nature Communications, vol. 6, 8093, pp. 8093. https://doi.org/10.1038/ncomms9093

TY - JOUR

T1 - A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

AU - Conde-Perez, Alejandro

AU - Gros, Gwendoline

AU - Longvert, Christine

AU - Pedersen, Malin

AU - Petit, Valérie

AU - Aktary, Zackie

AU - Viros, Amaya

AU - Gesbert, Franck

AU - Delmas, Véronique

AU - Rambow, Florian

AU - Bastian, Boris C.

AU - Campbell, Andrew D.

AU - Colombo, Sophie

AU - Puig, Isabel

AU - Bellacosa, Alfonso

AU - Sansom, Owen

AU - Marais, Richard

AU - Van Kempen, Leon C.L.T.

AU - Larue, Lionel

PY - 2015/8/26

Y1 - 2015/8/26

N2 - Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRAS Q61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β-catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

AB - Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRAS Q61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β-catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

KW - Animals

KW - Blotting, Western

KW - Cadherins/metabolism

KW - Caveolin 1/genetics

KW - Cell Line, Tumor

KW - Feedback, Physiological

KW - GTP Phosphohydrolases/genetics

KW - Glycogen Synthase Kinase 3 beta

KW - Glycogen Synthase Kinase 3/metabolism

KW - Humans

KW - Immunohistochemistry

KW - Melanocytes/metabolism

KW - Melanoma/genetics

KW - Membrane Proteins/genetics

KW - Mice

KW - Mice, Transgenic

KW - MicroRNAs

KW - Microscopy, Fluorescence

KW - PTEN Phosphohydrolase/genetics

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Prognosis

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Skin Neoplasms/genetics

KW - Transcriptional Activation/genetics

KW - beta Catenin/metabolism

UR - http://www.scopus.com/inward/record.url?scp=84940421711&partnerID=8YFLogxK

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000360354400001&DestLinkType=FullRecord&DestApp=WOS

U2 - 10.1038/ncomms9093

DO - 10.1038/ncomms9093

M3 - Article

C2 - 26307673

SN - 2041-1723

VL - 6

SP - 8093

JO - Nature Communications

JF - Nature Communications

M1 - 8093

ER -

A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this