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

Zheng Y., Sethi R., Mangala LS., Taylor C., Goldsmith J., Wang M., Masuda K., Karaminejadranjbar M., Mannion D., Miranda F., Herrero-Gonzalez S., Hellner K., Chen F., Alsaadi A., Albukhari A., Fotso DC., Yau C., Jiang D., Pradeep S., Rodriguez-Aguayo C., Lopez-Berestein G., Knapp S., Gray NS., Campo L., Myers KA., Dhar S., Ferguson D., Bast RC., Sood AK., von Delft F., Ahmed AA.

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.

DOI

10.1038/s41467-017-02811-7

Type

Journal article

Journal

Nat Commun

Publication Date

02/02/2018

Volume

9

Keywords

Animals, Cell Line, Tumor, Female, Humans, Intercellular Signaling Peptides and Proteins, Mice, Mice, Nude, Microscopy, Confocal, Microscopy, Fluorescence, Microtubules, Molecular Dynamics Simulation, Molecular Targeted Therapy, Neoplasm Transplantation, Nerve Tissue Proteins, Ovarian Neoplasms, Paclitaxel, Phosphorylation, Protein Multimerization, Protein-Tyrosine Kinases, RNA, Small Interfering, RNAi Therapeutics, Tubulin Modulators

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