Abstract
Epidermal growth factor receptor (EGFR) is an oncogenic receptor tyrosine kinase. Canonically, the tyrosine kinase activity of EGFR is regulated by its extracellular ligands. However, ligand-independent activation of EGFR exists in certain cancer cells, and the underlying mechanism remains to be defined. In this study, using PC3 and A549 cells as a model, we have found that, in the absence of extracellular ligands, a subpopulation of EGFR is constitutively active, which is needed for maintaining cell proliferation. Furthermore, we have found that fatty acid synthase (FASN)-dependent palmitoylation of EGFR is required for EGFR dimerization and kinase activation. Inhibition of FASN or palmitoyl acyltransferases reduced the activity and down-regulated the levels of EGFR, and sensitized cancer cells to EGFR tyrosine kinase inhibitors. It is concluded that EGFR can be activated intracellularly by FASN-dependent palmitoylation. This mechanism may serve as a new target for improving EGFR-based cancer therapy.
Highlights
Epidermal growth factor receptor (EGFR) is a member of the epidermal growth factor receptor tyrosine kinase family (ErbB family) that includes four members, EGFR (HER1), HER2/Neu, HER3 and HER4
In contrast to C225, AEE788, a small molecule of EGFR tyrosine kinase inhibitor (TKI), completely blocked both the EGF-induced and the constitutive activation of EGFR (Figure 1d), suggesting that EGFR constitutive activity in the absence of serum is not mediated by extracellular ligands and might be sustained by intracellular signaling
C225 blocked EGFinduced Akt and ERK phosphorylation but failed to block their basal activities, whereas AEE788 completely blocked both EGF-induced and basal activities of Akt and ERK. These results suggest that the ligand-independent constitutive activity of EGFR is required to sustain its downstream signaling pathways such as Akt and ERK
Summary
Epidermal growth factor receptor (EGFR) is a member of the epidermal growth factor receptor tyrosine kinase family (ErbB family) that includes four members, EGFR (HER1), HER2/Neu, HER3 and HER4. The ECD has a ligand binding domain (LBD); the TMD consists of 23 amino acids and anchors EGFR to the plasma membrane; and the ICD consists of the tyrosine kinase domain and a tyrosine rich domain that transduces signals to its downstream pathways such as the PI3K/Akt. Upon binding to its ligand, EGFR undergoes homo- or h eterodimerization with another ErbB member. Inhibition of the tyrosine kinase of EGFR by TKIs has produced responding rates range between 10–20% in lung cancer patients; all patients acquired resistance within few months after treatment,[4, 5] and prostate cancer, a type of cancer where EGFR is commonly overexpressed, is innately resistant to EGFR TKIs [6, 7]
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