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SORLA regulates endosomal trafficking and oncogenic fitness of HER2

Pietilä, Mika, Sahgal, Pranshu, Peuhu, Emilia, Jäntti, Niklas Z., Paatero, Ilkka, Närvä, Elisa, Al-Akhrass, Hussein, Lilja, Johanna, Georgiadou, Maria, Andersen, Olav M., Padzik, Artur, Sihto, Harri, Joensuu, Heikki, Blomqvist, Matias, Saarinen, Irena, Boström, Peter J., Taimen, Pekka, Ivaska, Johanna·2019·Nature Communications
DOI 10.1038/s41467-019-10275-0PMC PMC6538630

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Abstract

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1 ) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

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  • SORLA is known to regulate receptor protein homeostasis at the cell surface by modulating intracellular sorting of receptors to the TGN and endo-lysosomal compartments.

    “SORLA is known to regulate receptor protein homoeostasis at the cell surface by modulating intracellular sorting of receptors to the TGN and endo‐lysosomal compartments (Pietilä et al. 2019; Schmidt et al. 2017).”

    From The Alzheimer's Disease Gene <i>SORL1</i> Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Pietilä et al. 2019

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Metadata

Authors
Pietilä, M., Sahgal, P., Peuhu, E., Jäntti, N. Z., Paatero, I., Närvä, E., Al-Akhrass, H., Lilja, J., Georgiadou, M., Andersen, O. M., Padzik, A., Sihto, H., Joensuu, H., Blomqvist, M., Saarinen, I., Boström, P. J., Taimen, P., & Ivaska, J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-05-28
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-10275-0
PMC
PMC6538630
Cited by
75
References
3
Language
en
Licence

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