O'Regan, L., Barone, G., Adib, R. et al. (10 more authors) (2020) EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. Journal of Cell Science, 133 (9). jcs.241505. ISSN 0021-9533
Abstract
EML4-ALK is an oncogenic fusion present in ∼5% non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants with different patient outcomes. Here, we show in cell models that EML4-ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. It also recruits the NEK9 and NEK7 kinase to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4 as well as constitutive activation of NEK9 also perturb cell morphology and accelerate migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but not ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4-ALK patients. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through NEK9 and NEK7 leading to increased cell migration. This represents a novel actionable pathway that could drive metastatic disease progression in EML4-ALK lung cancer.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020. Published by The Company of Biologists Ltd. This is an author-produced version of a paper subsequently published in Journal of Cell Science. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | EML4-ALK; EML4; NEK9; NEK7; NSCLC; Microtubules; Cell migration; Metastasis |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Funding Information: | Funder Grant number CANCER RESEARCH UK C36435/A12102 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 27 Mar 2020 12:18 |
Last Modified: | 02 Dec 2021 13:07 |
Status: | Published |
Publisher: | The Company of Biologists |
Refereed: | Yes |
Identification Number: | 10.1242/jcs.241505 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:158768 |