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

Nat Cell Biol. 2015 Oct;17(10):1348-55. doi: 10.1038/ncb3222. Epub 2015 Aug 17.


Activation of epidermal growth factor receptor (EGFR), which occurs in many types of tumour, promotes tumour progression. However, no extracellular antagonist of human EGFR has been identified. We found that human macrophage migration inhibitory factor (MIF) is O-GlcNAcylated at Ser 112/Thr 113 at its carboxy terminus. The naturally secreted and O-GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF-induced EGFR activation, phosphorylation of ERK and c-Jun, cell invasion, proliferation and brain tumour formation. Activation of EGFR through mutation or its ligand binding enhances the secretion of MMP13, which degrades extracellular MIF, and results in abrogation of the negative regulation of MIF on EGFR. The finding that EGFR activation downregulates its antagonist in the tumour microenvironment represents an important feedforward mechanism for human tumour cells to enhance EGFR signalling and promote tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Immunoblotting
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Matrix Metalloproteinase 13 / metabolism
  • Mice, Nude
  • Microscopy, Fluorescence
  • Mutation
  • Phosphorylation / drug effects
  • Protein Binding
  • RNA Interference
  • Serine / metabolism
  • Survival Analysis
  • Threonine / genetics
  • Threonine / metabolism
  • Transplantation, Heterologous


  • Macrophage Migration-Inhibitory Factors
  • Threonine
  • Serine
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 13
  • Acetylglucosamine