The rak/frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor

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 _F_yn-_r_elated

_k_inase), 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. Access through your institution Buy or subscribe This is a preview of subscription content,

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ONCOGENIC FUNCTIONS Article Open access 09 July 2020 EGFR-DEPENDENT TYROSINE PHOSPHORYLATION OF INTEGRIN Β4 IS NOT REQUIRED FOR DOWNSTREAM SIGNALING EVENTS IN CANCER CELL LINES Article Open

access 21 April 2021 THE COMBINED ACTION OF THE INTRACELLULAR REGIONS REGULATES FGFR2 KINASE ACTIVITY Article Open access 14 July 2023 REFERENCES * Lemmon MA, Schlessinger J . Cell signaling

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references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA L Jin & R J Craven Authors * L Jin View author publications You can also search

for this author inPubMed Google Scholar * R J Craven View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to R J Craven.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on the Oncogene website

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associates with and internalizes the epidermal growth factor receptor. _Oncogene_ 33, 326–335 (2014). https://doi.org/10.1038/onc.2012.589 Download citation * Received: 14 May 2012 *

Revised: 30 October 2012 * Accepted: 31 October 2012 * Published: 14 January 2013 * Issue Date: 16 January 2014 * DOI: https://doi.org/10.1038/onc.2012.589 SHARE THIS ARTICLE Anyone you

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Springer Nature SharedIt content-sharing initiative KEYWORDS * signaling * tyrosine kinase * Rak * Frk * EGFR * SH2 * SH3