Journal article

INPP4B promotes PI3K alpha-dependent late endosome formation and Wnt/beta-catenin signaling in breast cancer

Samuel J Rodgers, Lisa M Ooms, Viola MJ Oorschot, Ralf B Schittenhelm, Elizabeth 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 Show all

NATURE COMMUNICATIONS | NATURE RESEARCH | Published : 2021

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 ..

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Grants

Awarded by NHMRC


Funding Acknowledgements

This work was supported by an NHMRC grant APP1104614. This study utilized the Monash Micro Imaging, Monash Histology Platform, Flowcore, Monash Proteomics & Metabolomics Facility, Monash Animal Research Platform, Micromon, Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Australia. The authors thank Joan Clark (Monash Ramaciotti Centre for Cryo Electron Microscopy) for excellent technical assistance.