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

Author

Listed:
  • Yiyan Zheng

    (University of Oxford
    John Radcliffe Hospital)

  • Ritika Sethi

    (University of Oxford)

  • Lingegowda S. Mangala

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Charlotte Taylor

    (University of Oxford
    John Radcliffe Hospital)

  • Juliet Goldsmith

    (University of Oxford
    John Radcliffe Hospital)

  • Ming Wang

    (University of Oxford
    John Radcliffe Hospital)

  • Kenta Masuda

    (University of Oxford
    John Radcliffe Hospital)

  • Eli M. Carrami

    (University of Oxford
    John Radcliffe Hospital)

  • David Mannion

    (University of Oxford
    John Radcliffe Hospital)

  • Fabrizio Miranda

    (University of Oxford
    John Radcliffe Hospital)

  • Sandra Herrero-Gonzalez

    (University of Oxford
    John Radcliffe Hospital)

  • Karin Hellner

    (University of Oxford
    John Radcliffe Hospital)

  • Fiona Chen

    (University of Oxford
    John Radcliffe Hospital)

  • Abdulkhaliq Alsaadi

    (University of Oxford
    John Radcliffe Hospital)

  • Ashwag Albukhari

    (University of Oxford
    John Radcliffe Hospital
    King Abdulaziz University)

  • Donatien Chedom Fotso

    (University of Oxford
    John Radcliffe Hospital)

  • Christopher Yau

    (Wellcome Trust Centre for Human Genetics and NIHR Biomedical Research Centre
    Department of Statistics)

  • Dahai Jiang

    (The University of Texas MD Anderson Cancer Center
    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
    University of Texas MD Anderson Cancer Center)

  • Gabriel Lopez-Berestein

    (The University of Texas MD Anderson Cancer Center
    University of Texas MD Anderson Cancer Center)

  • Stefan Knapp

    (University of Oxford
    Riedberg Campus)

  • Nathanael S. Gray

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • 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
    The University of Texas MD Anderson Cancer Center)

  • Frank von Delft

    (University of Oxford
    Harwell Science and Innovation Campus
    University of Johannesburg)

  • Ahmed Ashour Ahmed

    (University of Oxford
    John Radcliffe Hospital)

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.

Suggested Citation

  • Yiyan Zheng & Ritika Sethi & Lingegowda S. Mangala & Charlotte Taylor & Juliet Goldsmith & Ming Wang & Kenta Masuda & Eli M. Carrami & David Mannion & Fabrizio Miranda & Sandra Herrero-Gonzalez & Kari, 2018. "Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02811-7
    DOI: 10.1038/s41467-017-02811-7
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