INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
| Autor: | Matthew J. Eramo, Helen E. Abud, Lisa M Ooms, Samuel J. Rodgers, Elizabeth V. Nguyen, Sabryn A. Hamila, Natalie K. Rynkiewicz, Absorn Sriratana, Georg Ramm, Genevieve Kerr, Catriona McLean, Viola Oorschot, Ralf B. Schittenhelm, Sherene Loi, Andrew M. Ellisdon, Rajendra Gurung, Christina Anne Mitchell, Clare G Fedele, Antonella Papa, Roger J. Daly, Franco Caramia |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
0301 basic medicine Carcinogenesis General Physics and Astronomy medicine.disease_cause Mice Breast cancer 0302 clinical medicine Phosphatidylinositol Phosphates Breast Wnt Signaling Pathway Late endosome Multidisciplinary Chemistry Wnt signaling pathway Mechanisms of disease medicine.anatomical_structure 030220 oncology & carcinogenesis Female Class I Phosphatidylinositol 3-Kinases Endosome Science Antineoplastic Agents Breast Neoplasms Endosomes Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Phosphoinositol signalling Cell Line Tumor Lysosome medicine Animals Humans Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Oncogene Gene Expression Profiling rab7 GTP-Binding Proteins General Chemistry Xenograft Model Antitumor Assays Phosphoric Monoester Hydrolases Thiazoles 030104 developmental biology Tissue Array Analysis rab GTP-Binding Proteins Mutation Proteolysis Cancer research Lysosomes |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The PI(3,4)P2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA-mutant ER+ breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink