SORLA regulates endosomal trafficking and oncogenic fitness of HER2.

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.
Authors	Mika Pietilä, Pranshu Sahgal, Emilia Peuhu, Niklas Z Jäntti, Ilkka Paatero, Elisa Närvä, Hussein Al-Akhrass, Johanna Lilja, Maria Georgiadou, Olav M Andersen, Artur Padzik, Harri Sihto, Heikki Joensuu, Matias Blomqvist, Irena Saarinen, Peter J Boström, Pekka Taimen, Johanna Ivaska
Journal	Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 2340 (05 28 2019) ISSN: 2041-1723 [Electronic] England
PMID	31138794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	LDL-Receptor Related Proteins Membrane Transport Proteins SORL1 protein, human ERBB2 protein, human Receptor, ErbB-2
Topics	Animals Breast Neoplasms (genetics, metabolism) Carcinoma, Intraductal, Noninfiltrating (genetics, metabolism) Carcinoma, Transitional Cell (genetics, metabolism) Cell Line, Tumor Cell Membrane (metabolism) Cell Proliferation Endosomes (metabolism) Female Humans LDL-Receptor Related Proteins (genetics, metabolism) Lysosomes (metabolism) MCF-7 Cells Membrane Transport Proteins (genetics, metabolism) Mice Mice, Nude Neoplasm Transplantation Protein Transport Receptor, ErbB-2 (metabolism) Urinary Bladder Neoplasms (genetics, metabolism)

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