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

Samuel J. Rodgers, Lisa M. Ooms, Viola M. J. Oorschot, Ralf B. Schittenhelm, Elizabeth V. Nguyen, Sabryn A. Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J. Eramo, Absorn Sriratana, Clare G. Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E. Abud, Georg Ramm, Antonella Papa, Andrew M. Ellisdon, Roger J. Daly, Catriona A. McLean and Christina A. Mitchell ()
Additional contact information
Samuel J. Rodgers: Monash University
Lisa M. Ooms: Monash University
Viola M. J. Oorschot: Monash University
Ralf B. Schittenhelm: Monash University
Elizabeth V. Nguyen: Monash University
Sabryn A. Hamila: Monash University
Natalie Rynkiewicz: Monash University
Rajendra Gurung: Monash University
Matthew J. Eramo: Monash University
Absorn Sriratana: Monash University
Clare G. Fedele: Monash University
Franco Caramia: University of Melbourne
Sherene Loi: University of Melbourne
Genevieve Kerr: Monash University
Helen E. Abud: Monash University
Georg Ramm: Monash University
Antonella Papa: Monash University
Andrew M. Ellisdon: Monash University
Roger J. Daly: Monash University
Catriona A. McLean: Department of Anatomical Pathology, Alfred Hospital
Christina A. Mitchell: Monash University

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 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)P2 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)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23241-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23241-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23241-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().