TY - JOUR
T1 - Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation
AU - Zheng, Yiyan
AU - Sethi, Ritika
AU - Mangala, Lingegowda S.
AU - Taylor, Charlotte
AU - Goldsmith, Juliet
AU - Wang, Ming
AU - Masuda, Kenta
AU - Karaminejadranjbar, Mohammad
AU - Mannion, David
AU - Miranda, Fabrizio
AU - Herrero-Gonzalez, Sandra
AU - Hellner, Karin
AU - Chen, Fiona
AU - Alsaadi, Abdulkhaliq
AU - Albukhari, Ashwag
AU - Fotso, Donatien Chedom
AU - Yau, Christopher
AU - Jiang, Dahai
AU - Pradeep, Sunila
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Knapp, Stefan
AU - Gray, Nathanael S.
AU - Campo, Leticia
AU - Myers, Kevin A.
AU - Dhar, Sunanda
AU - Ferguson, David
AU - Bast, Robert C.
AU - Sood, Anil K.
AU - Von Delft, Frank
AU - Ahmed, Ahmed Ashour
N1 - Funding Information:
We thank the Oxford Centre for Histopathology Research for their help with processing tissue arrays. We thank Errin Johnson, Anna Pielach, and the Dunn School Bioimaging Facility for technical help with the electron microscopy work. We thank Christoffer Lagerholm and Esther Garcia in Wolfson Imaging Centre Oxford for technical help in total internal reflection fluorescence microscopy (TIRFM) work. We thank Dr. David Staunton at the Department of Biochemistry, University of Oxford, for his technical help and assistance in performing and analyzing circular dichroism spectrophotometry experiments. This work was funded by Target Ovarian Cancer, the Medical Research Council, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Experimental Cancer Medicine Centre, and the Helen Clarke Fund.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02811-7
DO - 10.1038/s41467-017-02811-7
M3 - Article
C2 - 29396402
AN - SCOPUS:85041609909
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 476
ER -
