Abstract
MIF inhibition of EGFR is ablated by EGFR activation–induced secretion of MMP13.
Major finding: MIF inhibition of EGFR is ablated by EGFR activation–induced secretion of MMP13.
Mechanism: Secreted O-GlcNAcylated MIF binds to EGFR and prevents EGF-mediated activation of EGFR.
Impact: MIF degradation in the tumor microenvironment amplifies EGFR activation to promote tumorigenesis.
EGFR signaling is activated in multiple tumor types by overexpression or mutations, and is modulated by the induction of early and late regulatory loops; however, an extracellular antagonist for human EGFR has not yet been identified. Co-expression of amplified wild-type EGFR and EGFRvIII, a constitutively activated truncation mutant of EGFR that signals via both autocrine and paracrine mechanisms, occurs in a subset of glioblastoma multiforme (GBM) tumors and results in the cooperative activation of oncogenic signaling pathways. Zheng and colleagues investigated the role of macrophage migration inhibitory factor (MIF), an immunostimulatory cytokine whose function in tumorigenesis may be context-dependent, in the regulation of EGFR signaling. Extracellular MIF was downregulated in the presence of either activated wild-type EGFR or EGFRvIII in GBM and other cancer cell lines. Activated EGFR signaling enhanced the secretion of extracellular matrix metalloproteinase 13 (MMP13), which resulted in MMP13-mediated degradation of MIF. Analysis of MIF function revealed that secreted extracellular MIF competitively bound to EGFR and prevented EGF-mediated activation of EGFR. Of note, the inhibition of EGF-activated EGFR signaling by MIF was dependent on the post-translational modification of MIF by O-linked β-N-acetylglucosamine at Ser112 and Thr113. Consistent with these findings, in an intracranial mouse model of GBM, the presence of O-GlcNAcylated MIF inhibited tumor cell proliferation and invasion and increased survival, whereas unmodified MIF or knockdown of MIF resulted in rapid tumorigenesis and decreased survival. Taken together, these findings show that MIF is an extracellular antagonist of EGFR and describe an important protumorigenic autocrine and paracrine mechanism that is driven by activated EGFR signaling in tumors and mediated by downregulation of MIF in the tumor microenvironment.
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