Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

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Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

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Title: Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation
Author: Zheng, Yiyan; Sethi, Ritika; Mangala, Lingegowda S.; Taylor, Charlotte; Goldsmith, Juliet; Wang, Ming; Masuda, Kenta; Karaminejadranjbar, Mohammad; Mannion, David; Miranda, Fabrizio; Herrero-Gonzalez, Sandra; Hellner, Karin; Chen, Fiona; Alsaadi, Abdulkhaliq; Albukhari, Ashwag; Fotso, Donatien Chedom; Yau, Christopher; Jiang, Dahai; Pradeep, Sunila; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Knapp, Stefan; Gray, Nathanael S.; Campo, Leticia; Myers, Kevin A.; Dhar, Sunanda; Ferguson, David; Bast, Robert C.; Sood, Anil K.; von Delft, Frank; Ahmed, Ahmed Ashour

Note: Order does not necessarily reflect citation order of authors.

Citation: Zheng, Y., R. Sethi, L. S. Mangala, C. Taylor, J. Goldsmith, M. Wang, K. Masuda, et al. 2018. “Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation.” Nature Communications 9 (1): 476. doi:10.1038/s41467-017-02811-7. http://dx.doi.org/10.1038/s41467-017-02811-7.
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Abstract: Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.
Published Version: doi:10.1038/s41467-017-02811-7
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797184/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:35015036
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