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Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR

Oncogene volume 31, pages 4372–4383 (2012)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy.

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Acknowledgements

We thank Dr Mark R Crompton (University of London) for providing the Brk DNA constructs, Dr Steven P Ethier (Karmanos Cancer Institute) for the SUM series of cell lines and Stephanie Deming (Department of Scientific Publications, MD Anderson Cancer Center) for editing the manuscript. This work was supported in part by grants from the US Congressionally Directed Medical Research Programs of the Department of Defense (W81XWH-06-1-0544 and W81XWH-07-1-0526), the Breast Cancer Research Foundation and the National Institutes of Health (5R01CA129036) and MD Anderson's NIH Cancer Center Support Grant (CA016672).

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Authors and Affiliations

  1. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Li, Y Lu, K Liang & Z Fan

  2. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J-M Hsu & M-C Hung

  3. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Albarracin

  4. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G B Mills

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  1. X Li
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Correspondence to Z Fan.

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Li, X., Lu, Y., Liang, K. et al. Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. Oncogene 31, 4372–4383 (2012). https://doi.org/10.1038/onc.2011.608

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