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

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.