The mesenchymal morphology of cells expressing the EML4–ALK V3 oncogene is dependent on phosphorylation of Eg5 by NEK7
Echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) oncogenic fusion proteins are found in approximately 5% of non–small cell lung cancers. Different EML4–ALK fusion variants exist with variant 3 (V3) being associated with a significantly higher risk than other c...
| Autores: | , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/365776 |
| Acceso en línea: | http://hdl.handle.net/10261/365776 |
| Access Level: | acceso abierto |
| Palabra clave: | EML4–ALK NEK7 NEK9 Microtubules Eg5 Eg5 inhibitors NSCLC |
| Sumario: | Echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) oncogenic fusion proteins are found in approximately 5% of non–small cell lung cancers. Different EML4–ALK fusion variants exist with variant 3 (V3) being associated with a significantly higher risk than other common variants, such as variant 1 (V1). Patients with V3 respond less well to targeted ALK inhibitors, have accelerated rates of metastasis, and have poorer overall survival. A pathway has been described downstream of EML4–ALK V3 that is independent of ALK catalytic activity but dependent on the NEK9 and NEK7 kinases. It has been proposed that assembly of an EML4–ALK V3–NEK9–NEK7 complex on microtubules leads to cells developing a mesenchymal-like morphology and exhibiting enhanced migration. However, downstream targets of this complex remain unknown. Here, we show that the microtubule-based kinesin, Eg5, is recruited to interphase microtubules in cells expressing EML4–ALK V3, whereas chemical inhibition of Eg5 reverses the mesenchymal morphology of cells. Furthermore, we show that depletion of NEK7 interferes with Eg5 recruitment to microtubules in cells expressing EML4–ALK V3 and cell length is reduced, but this is reversed by coexpression of a phosphomimetic mutant of Eg5, in a site, S1033, phosphorylated by NEK7. Intriguingly, we also found that expression of Eg5-S1033D led to cells expressing EML4–ALK V1 adopting a more mesenchymal-like morphology. Together, we propose that Eg5 acts as a substrate of NEK7 in cells expressing EML4–ALK V3 and Eg5 phosphorylation promotes the mesenchymal morphology typical of these cells. |
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