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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
Nat Commun 9 476 (2018)
Cited: 25 times
EuropePMC logo PMID: 29396402

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.

Articles - 5mle mentioned but not cited (2)

  1. 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, Carrami EM, 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. Nat Commun 9 476 (2018)
  2. SUMO on CRMPs - wrestling for pain? Baumann A, Kursula P. Channels (Austin) 11 265-267 (2017)


Reviews citing this publication (1)

  1. Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions. Moutal A, White KA, Chefdeville A, Laufmann RN, Vitiello PF, Feinstein D, Weimer JM, Khanna R. Mol Neurobiol 56 6736-6755 (2019)

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  2. Taxane resistance in prostate cancer is mediated by decreased drug-target engagement. Gjyrezi A, Xie F, Voznesensky O, Khanna P, Calagua C, Bai Y, Kung J, Wu J, Corey E, Montgomery B, Mace S, Gianolio DA, Bubley GJ, Balk SP, Giannakakou P, Bhatt RS. J Clin Invest 130 3287-3298 (2020)
  3. Cortical anchoring of the microtubule cytoskeleton is essential for neuron polarity. He L, Kooistra R, Das R, Oudejans E, van Leen E, Ziegler J, Portegies S, de Haan B, van Regteren Altena A, Stucchi R, Altelaar AM, Wieser S, Krieg M, Hoogenraad CC, Harterink M. Elife 9 e55111 (2020)
  4. PI3K/AKT/GSK3β/CRMP-2-mediated neuroplasticity in depression induced by stress. Wu Z, Wang G, Wei Y, Xiao L, Wang H. Neuroreport 29 1256-1263 (2018)
  5. Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Yang H, Mao W, Rodriguez-Aguayo C, Mangala LS, Bartholomeusz G, Iles LR, Jennings NB, Ahmed AA, Sood AK, Lopez-Berestein G, Lu Z, Bast RC. Clin Cancer Res 24 5072-5084 (2018)
  6. AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain. Yu H, Shin SM, Xiang H, Chao D, Cai Y, Xu H, Khanna R, Pan B, Hogan QH. Gene Ther 26 308-323 (2019)
  7. Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis. Toyoshima M, Jiang X, Ogawa T, Ohnishi T, Yoshihara S, Balan S, Yoshikawa T, Hirokawa N. Life Sci Alliance 2 e201900478 (2019)
  8. MiR-93 is related to poor prognosis in pancreatic cancer and promotes tumor progression by targeting microtubule dynamics. Vila-Navarro E, Fernandez-Castañer E, Rovira-Rigau M, Raimondi G, Vila-Casadesus M, Lozano JJ, Soubeyran P, Iovanna J, Castells A, Fillat C, Gironella M. Oncogenesis 9 43 (2020)
  9. Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2. Duciel L, Anezo O, Mandal K, Laurent C, Planque N, Coquelle FM, Gentien D, Manneville JB, Saule S. Sci Rep 9 2990 (2019)
  10. CRMP/UNC-33 organizes microtubule bundles for KIF5-mediated mitochondrial distribution to axon. Chen YC, Huang HR, Hsu CH, Ou CY. PLoS Genet 17 e1009360 (2021)
  11. DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma. Wu YJ, Nai AT, He GC, Xiao F, Li ZM, Tang SY, Liu YP, Ai XH. World J Surg Oncol 19 274 (2021)
  12. FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells. Zhang Y, Xiong X, Zhu Q, Zhang J, Chen S, Wang Y, Cao J, Chen L, Hou L, Zhao X, Hao P, Chen J, Zhuang M, Li D, Fan G. Elife 11 e76183 (2022)
  13. Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories. Cuveillier C, Boulan B, Ravanello C, Denarier E, Deloulme JC, Gory-Fauré S, Delphin C, Bosc C, Arnal I, Andrieux A. Front Mol Neurosci 14 665693 (2021)
  14. Inhibition of Ubc9-Induced CRMP2 SUMOylation Disrupts Glioblastoma Cell Proliferation. Wang L, Ji S. J Mol Neurosci 69 391-398 (2019)
  15. Arsenic trioxide disturbs the LIS1/NDEL1/dynein microtubule dynamic complex by disrupting the CLIP170 zinc finger in head and neck cancer. Gao L, Xue B, Xiang B, Liu KJ. Toxicol Appl Pharmacol 403 115158 (2020)
  16. CD147 supports paclitaxel resistance via interacting with RanBP1. Nan G, Zhao SH, Wang T, Chao D, Tian RF, Wang WJ, Fu X, Lin P, Guo T, Wang B, Sun XX, Chen X, Chen ZN, Wang SJ, Cui HY. Oncogene 41 983-996 (2022)
  17. Cortical transcriptome analysis after spinal cord injury reveals the regenerative mechanism of central nervous system in CRMP2 knock-in mice. Sugeno A, Piao W, Yamazaki M, Takahashi K, Arikawa K, Matsunaga H, Hosokawa M, Tominaga D, Goshima Y, Takeyama H, Ohshima T. Neural Regen Res 16 1258-1265 (2021)
  18. Dihydropyrimidinase-related protein 5 controls glioblastoma stem cell characteristics as a biomarker of proneural-subtype glioblastoma stem cells. Park MG, Seo S, Ham SW, Choi SH, Kim H. Oncol Lett 20 1153-1162 (2020)
  19. Swimming exercise reverses chronic unpredictable mild stress-induced depression-like behaviors and alleviates neuroinflammation and collapsing response mediator protein-2-mediated neuroplasticity injury in adult male mice. Xie Y, Wu Z, Sun L, Zhou L, Xiao L, Wang H, Wang G. Neuroreport 33 272-282 (2022)
  20. Brief Maternal Separation Promotes Resilience to Anxiety-like and Depressive-like Behaviors in Female C57BL/6J Offspring with Imiquimod-Induced Psoriasis. Zhou L, Wu Z, Li Y, Xiao L, Wang H, Wang G. Brain Sci 12 1250 (2022)
  21. Matrin3 regulates mitotic spindle dynamics by controlling alternative splicing of CDC14B. Muys BR, Shrestha RL, Anastasakis DG, Pongor L, Li XL, Grammatikakis I, Polash A, Chari R, Gorospe M, Harris CC, Aladjem MI, Basrai MA, Hafner M, Lal A. Cell Rep 42 112260 (2023)
  22. Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams. Zhou L, Wu Z, Zhao D, Wang G, Xiao L, Wang H, Xie Y, Sun L. J Psychiatry Neurosci 48 E154-E170 (2023)


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