Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Epidermal growth factor receptor (EGFR) activation drives tumor progression in many cancers.
• An extracellular antagonist for human EGFR has not been previously identified.

Purpose of the Study:

• To identify and characterize an extracellular antagonist of human EGFR.
• To elucidate the mechanism by which this antagonist regulates EGFR signaling in tumors.

Main Methods:

• Investigated the post-translational modification of macrophage migration inhibitory factor (MIF).
• Assessed the binding of O-GlcNAcylated MIF to EGFR and its effect on EGFR activation.
• Analyzed the impact of MIF on EGFR-mediated signaling pathways (ERK, c-Jun) and cellular processes (invasion, proliferation).
• Examined the role of matrix metalloproteinase 13 (MMP13) in regulating MIF stability in the tumor microenvironment.

Main Results:

• Human MIF undergoes O-GlcNAcylation at its carboxy terminus (Ser 112/Thr 113).
• O-GlcNAcylated MIF binds to EGFR, inhibiting EGF binding and subsequent EGFR activation.
• MIF antagonizes EGFR-induced ERK and c-Jun phosphorylation, cell invasion, proliferation, and brain tumor formation.
• EGFR activation stimulates MMP13 secretion, which degrades extracellular MIF, thereby removing the negative regulation of MIF on EGFR.
• This creates a feedforward loop where EGFR activation promotes its own signaling by degrading its antagonist.

Conclusions:

• O-GlcNAcylated MIF is a novel extracellular antagonist of human EGFR.
• EGFR signaling promotes its own amplification through MMP13-mediated degradation of MIF in the tumor microenvironment.
• Targeting MIF or MMP13 could represent a therapeutic strategy for EGFR-driven tumors.