Abstract
c-Src is upregulated in various human cancers, suggesting its role in malignant progression. However, the molecular circuits of c-Src oncogenic signaling remain elusive. Here we show that Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we showed that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. In this study, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer was also crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer activation was required for tumorigenesis and invasiveness in some cancer cells in which c-Src is upregulated. We propose that the Src–Fer axis represents a new therapeutic target for treatment of a subset of human cancers.
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Acknowledgements
We thank T Akagi for pCX4 vector, N Mochizuki for a series of Fer expression vectors, A Imamoto for SFC− cells, K Saito for technical assistance with the LC-MS/MS analysis and JA Cooper for critical reading and editing of the manuscript. LC-MS/MS analysis was performed in the DNA-chip Development Centre for Infectious Diseases (RIMD, Osaka University). This work was supported by the Exciting Leading-Edge Research Project and the MEET Project at Osaka University; grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for Young Scientists (A); and The Yasuda Medical Foundation.
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Oneyama, C., Yoshikawa, Y., Ninomiya, Y. et al. Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Oncogene 35, 501–512 (2016). https://doi.org/10.1038/onc.2015.110
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DOI: https://doi.org/10.1038/onc.2015.110
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