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INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P(2) to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-muta...

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Autores principales: Rodgers, Samuel J., Ooms, Lisa M., Oorschot, Viola M. J., Schittenhelm, Ralf B., Nguyen, Elizabeth V., Hamila, Sabryn A., Rynkiewicz, Natalie, Gurung, Rajendra, Eramo, Matthew J., Sriratana, Absorn, Fedele, Clare G., Caramia, Franco, Loi, Sherene, Kerr, Genevieve, Abud, Helen E., Ramm, Georg, Papa, Antonella, Ellisdon, Andrew M., Daly, Roger J., McLean, Catriona A., Mitchell, Christina A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149851/
https://www.ncbi.nlm.nih.gov/pubmed/34035258
http://dx.doi.org/10.1038/s41467-021-23241-6
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author Rodgers, Samuel J.
Ooms, Lisa M.
Oorschot, Viola M. J.
Schittenhelm, Ralf B.
Nguyen, Elizabeth V.
Hamila, Sabryn A.
Rynkiewicz, Natalie
Gurung, Rajendra
Eramo, Matthew J.
Sriratana, Absorn
Fedele, Clare G.
Caramia, Franco
Loi, Sherene
Kerr, Genevieve
Abud, Helen E.
Ramm, Georg
Papa, Antonella
Ellisdon, Andrew M.
Daly, Roger J.
McLean, Catriona A.
Mitchell, Christina A.
author_facet Rodgers, Samuel J.
Ooms, Lisa M.
Oorschot, Viola M. J.
Schittenhelm, Ralf B.
Nguyen, Elizabeth V.
Hamila, Sabryn A.
Rynkiewicz, Natalie
Gurung, Rajendra
Eramo, Matthew J.
Sriratana, Absorn
Fedele, Clare G.
Caramia, Franco
Loi, Sherene
Kerr, Genevieve
Abud, Helen E.
Ramm, Georg
Papa, Antonella
Ellisdon, Andrew M.
Daly, Roger J.
McLean, Catriona A.
Mitchell, Christina A.
author_sort Rodgers, Samuel J.
collection PubMed
description INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P(2) to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER(+) breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER(+) breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P(2) to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER(+) breast cancer via PI(3,4)P(2) to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
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spelling pubmed-81498512021-06-11 INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer Rodgers, Samuel J. Ooms, Lisa M. Oorschot, Viola M. J. Schittenhelm, Ralf B. Nguyen, Elizabeth V. Hamila, Sabryn A. Rynkiewicz, Natalie Gurung, Rajendra Eramo, Matthew J. Sriratana, Absorn Fedele, Clare G. Caramia, Franco Loi, Sherene Kerr, Genevieve Abud, Helen E. Ramm, Georg Papa, Antonella Ellisdon, Andrew M. Daly, Roger J. McLean, Catriona A. Mitchell, Christina A. Nat Commun Article INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P(2) to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER(+) breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER(+) breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P(2) to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER(+) breast cancer via PI(3,4)P(2) to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies. Nature Publishing Group UK 2021-05-25 /pmc/articles/PMC8149851/ /pubmed/34035258 http://dx.doi.org/10.1038/s41467-021-23241-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Rodgers, Samuel J.
Ooms, Lisa M.
Oorschot, Viola M. J.
Schittenhelm, Ralf B.
Nguyen, Elizabeth V.
Hamila, Sabryn A.
Rynkiewicz, Natalie
Gurung, Rajendra
Eramo, Matthew J.
Sriratana, Absorn
Fedele, Clare G.
Caramia, Franco
Loi, Sherene
Kerr, Genevieve
Abud, Helen E.
Ramm, Georg
Papa, Antonella
Ellisdon, Andrew M.
Daly, Roger J.
McLean, Catriona A.
Mitchell, Christina A.
INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title_full INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title_fullStr INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title_full_unstemmed INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title_short INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
title_sort inpp4b promotes pi3kα-dependent late endosome formation and wnt/β-catenin signaling in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149851/
https://www.ncbi.nlm.nih.gov/pubmed/34035258
http://dx.doi.org/10.1038/s41467-021-23241-6
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