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

• DOI: 10.1038/s41467-017-02811-7
• Publication Date: 2018-01-29T19:14:02Z
• Authors: Yiyan Zheng; Ritika Sethi; Lingegowda S. Man...; Charlotte Taylor; Juliet Goldsmith; Ming Wang; Kenta Masuda; Eli M. Carrami; David Mannion; Fabrizio Miranda; Sandra Herrero-Go...; Karin Hellner; Fiona Chen; Abdulkhaliq Alsaadi; Ashwag Albukhari; Donatien Chedom F...; Christopher Yau; Dahai Jiang; Sunila Pradeep; Cristian Rodrigue...; Gabriel Lopez-Ber...; Stefan Knapp; Nathanael S. Gray; Leticia Campo; Kevin A. Myers; Sunanda Dhar; David Ferguson; Robert C. Bast; Anil K. Sood; Frank von Delft; Ahmed Ashour Ahmed
• Keywords: 0301 basic medicine; 570; Paclitaxel; Science; Mice, Nude; Nerve Tissue Proteins; Molecular Dynamics Simulation; Microtubules; Article; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Molecular Targeted Therapy; Phosphorylation; RNA, Small Interfering; Ovarian Neoplasms; Microscopy, Confocal; Q; Protein-Tyrosine Kinases; 3. Good health; Microscopy, Fluorescence; Intercellular Signaling Peptides and Proteins; Female; Protein Multimerization; Neoplasm Transplantation

AbstractThough 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.