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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.
Document Type
Article
Publication Date
1-16-2014
Digital Object Identifier (DOI)
http://dx.doi.org/10.1038/onc.2012.589
Repository Citation
Jin, Ling and Craven, Rolf J., "The Rak/Frk Tyrosine Kinase Associates With and Internalizes the Epidermal Growth Factor Receptor" (2014). Pharmacology and Nutritional Sciences Faculty Publications. 25.
https://uknowledge.uky.edu/pharmacol_facpub/25
Included in
Medical Nutrition Commons, Medical Pharmacology Commons, Pharmacology, Toxicology and Environmental Health Commons
Notes/Citation Information
Published in Oncogene, v. 33, issue 3, p. 326-335.
The document available for download is the authors' post-peer-review final draft of the article.