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

Author

Listed:
  • Samuel J. Rodgers

    (Monash University
    Monash University)

  • Lisa M. Ooms

    (Monash University
    Monash University)

  • Viola M. J. Oorschot

    (Monash University
    Electron Microscopy Core Facility, European Molecular Biology Laboratory)

  • Ralf B. Schittenhelm

    (Monash University)

  • Elizabeth V. Nguyen

    (Monash University
    Monash University)

  • Sabryn A. Hamila

    (Monash University
    Monash University)

  • Natalie Rynkiewicz

    (Monash University
    Babraham Institute)

  • Rajendra Gurung

    (Monash University
    Monash University)

  • Matthew J. Eramo

    (Monash University
    Monash University)

  • Absorn Sriratana

    (Monash University
    Monash University)

  • Clare G. Fedele

    (Monash University
    University of Melbourne)

  • Franco Caramia

    (University of Melbourne)

  • Sherene Loi

    (University of Melbourne)

  • Genevieve Kerr

    (Monash University
    Monash University)

  • Helen E. Abud

    (Monash University
    Monash University)

  • Georg Ramm

    (Monash University
    Monash University
    Monash University)

  • Antonella Papa

    (Monash University
    Monash University)

  • Andrew M. Ellisdon

    (Monash University
    Monash University
    Monash University)

  • Roger J. Daly

    (Monash University
    Monash University)

  • Catriona A. McLean

    (Department of Anatomical Pathology, Alfred Hospital)

  • Christina A. Mitchell

    (Monash University
    Monash University)

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.

Suggested Citation

  • 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 & C, 2021. "INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23241-6
    DOI: 10.1038/s41467-021-23241-6
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    Cited by:

    1. Harrison M. York & Kunaal Joshi & Charles S. Wright & Laura Z. Kreplin & Samuel J. Rodgers & Ullhas K. Moorthi & Hetvi Gandhi & Abhishek Patil & Christina A. Mitchell & Srividya Iyer-Biswas & Senthil , 2023. "Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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