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The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor

Oncogene volume 33, pages 326–335 (2014)Cite this article

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Abstract

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates with epidermal growth factor receptor (EGFR), increasing in activity and EGFR binding after EGF stimulation, when it decreases the pool of EGFR present at the plasma membrane. EGFR–Rak binding is direct, requires the SH2 and SH3 domains of Rak/Frk for efficient complex formation and is not dependent on the Grb2 adaptor protein. EGFR mutations are associated with increased EGFR activity and tumorigenicity, and we found that Rak/Frk associates preferentially with an EGFR exon 19 mutant, EGFRΔ747–749/A750P, compared with wild-type EGFR. Furthermore, Rak/Frk inhibited mutant EGFR phosphorylation at an activating site and dramatically decreased the levels of EGFRΔ747–749/A750P from the plasma membrane. Taken together, the results suggest that Rak/Frk inhibits EGFR signaling in cancer cells and has elevated activity against EGFR exon 19 mutants.

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Acknowledgements

This work was supported by the Kentucky Lung Cancer Research Program, cycle 9. We thank Drs Gengxian Shi and Doug Andres for advice and reagents, Mary Gail Engle of the University of Kentucky Imaging Core Facility for expertise in microscopy and Woodrow Friend for reading of the manuscript.

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  1. Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    L Jin & R J Craven

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Correspondence to R J Craven.

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Jin, L., Craven, R. The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor. Oncogene 33, 326–335 (2014). https://doi.org/10.1038/onc.2012.589

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