HER2 expression defines unique requirements for flotillin and c-Src for EGFR signaling

Abstract

The epidermal growth factor receptor (EGFR) controls many cellular functions. Upon binding its ligand, the receptor undergoes dimerization, phosphorylation, and activation of signals including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway. While some studies indicated that EGFR signaling may be controlled by signal enrichment within membrane raft nanodomains, others have found a limited effect of membrane raft disruption on EGFR signaling, suggesting that specific factor(s) may define context-specific control of EGFR signaling by membrane rafts. Ligand-bound EGFR can homodimerize, or instead undergo heterodimerization with the related receptor HER2 when the latter is expressed. We examined how EGFR signaling in the presence of HER2 distinctly requires membrane raft nanodomains. Induction of HER2 expression altered EGFR signaling duration consistent with EGFR/HER2 heterodimer formation. EGFR and c-Src localized within plasma membrane structures demarked by flotillin, a membrane raft protein, selectively in HER2-expressing cells. Consistently, HER2-expressing cells, but not cells lacking HER2, were dependent on flotillin and c-Src for EGFR signaling leading to Akt activation and cell proliferation. Hence, HER2 expression establishes the requirement of EGFR signaling for flotillin membrane rafts and c-Src, leading to Akt activation. Summary statementThe role of membrane rafts in EGFR signaling may be context-specific. We find that the related receptor HER2 defines unique signaling requirements for EGFR for membrane rafts, flotillin, and c-Src.