Adaptor protein APPL1 interacts with EGFR to orchestrate EGF-stimulated signaling

Epidermal growth factor receptor (EGFR) mediates multiple signaling pathways that regulate cell migration, proliferation, and differentiation. Adaptor protein APPL1 has been reported to function as a downstream effector of EGFR signaling pathway. However, molecular mechanisms underlying the role of APPL1 downstream of EGFR signaling remains elusive. Here, we identified APPL1 as a critical molecule that interacts with EGFR. Suppression of APPL1 by siRNA inhibited EGF-stimulated Akt phosphorylation. Functionally, EGF stimulation of cells caused phosphorylation of APPL1 at Ser636, which subsequently promoted the interaction between APPL1 and EGFR, indicating that APPL1 sensitizes EGF stimulation by acting at a site downstream of the EGFR signaling. Importantly, non-phosphorylatable mutant of APPL1 reduced cell migration compared with wild-type APPL1 in an Akt-dependent manner. Our study reveals a novel function of APPL1 in EGF signaling and defines a novel molecular mechanism by which phosphorylation of APPL1 upon EGF stimulation regulates cell migration underlying EGF-stimulated Akt pathway.