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

DOI: 10.1038/s41467-017-02811-7 DOI Help

Authors: Yiyan Zheng (University of Oxford) , Ritika Sethi (University of Oxford) , Lingegowda S. Mangala (The University of Texas MD Anderson Cancer Center) , Charlotte Taylor (University of Oxford) , Juliet Goldsmith (University of Oxford) , Ming Wang (University of Oxford) , Kenta Masuda (University of Oxford) , Mohammad Karaminejadranjbar (University of Oxford) , David Mannion (University of Oxford) , Fabrizio Miranda (University of Oxford) , Sandra Herrero-Gonzalez (University of Oxford) , Karin Hellner (University of Oxford) , Fiona Chen (University of Oxford) , Abdulkhaliq Alsaadi (University of Oxford) , Ashwag Albukhari (University of Oxford) , Donatien Chedom Fotso (University of Oxford) , Christopher Yau (University of Oxford) , Dahai Jiang (The University of Texas MD Anderson Cancer Center) , Sunila Pradeep (The University of Texas MD Anderson Cancer Center) , Cristian Rodriguez-Aguayo (The University of Texas MD Anderson Cancer Center) , Gabriel Lopez-Berestein (The University of Texas MD Anderson Cancer Center) , Stefan Knapp (Goethe-University Frankfurt) , Nathanael S. Gray (Harvard Medical School) , Leticia Campo (University of Oxford) , Kevin A. Myers (University of Oxford) , Sunanda Dhar (Oxford University Hospitals) , David Ferguson (Oxford University Hospitals) , Robert C. Bast (University of Texas MD Anderson Cancer Center) , Anil K. Sood (The University of Texas MD Anderson Cancer Center) , Frank Von Delft (Diamond Light Source; University of Johannesburg) , Ahmed Ashour Ahmed (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: February 2018

Open Access Open Access

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.

Journal Keywords: Kinases; Ovarian cancer

Diamond Keywords: Ovarian Cancer

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 05/02/2018 08:41

Documents:
s41467-017-02811-7.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)