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Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression

Oncogene volume 35, pages 501–512 (2016)Cite this article

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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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Authors and Affiliations

  1. Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    C Oneyama, Y Yoshikawa, Y Ninomiya, T Iino & M Okada

  2. Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan

    S Tsukita

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  1. C Oneyama
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Correspondence to C Oneyama.

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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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