Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer that is driven by aberrant signaling of growth factor receptors, particularly the epidermal growth factor receptor (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosome-mediated degradation, although the molecular mechanisms governing such regulation, particularly in the context of cancer, remain poorly delineated. Here, high-resolution genomic profiles of GBM identified a highly recurrent focal 1p36 deletion encompassing the putative tumor suppressor gene, Mig-6. We show that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation. Mechanistically, this effect is mediated by the binding of Mig-6 to a SNARE protein STX8, a protein known to be required for late endosome trafficking. Thus, Mig-6 functions to ensure recruitment of internalized receptor to late endosomes and subsequently the lysosomal degradation compartment through its ability to specifically link EGFR and STX8 during ligand-stimulated EGFR trafficking. In GBM, the highly frequent loss of Mig-6 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, these data uncover a unique tumor suppression mechanism involving the regulation of receptor trafficking.

Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

“…1p36 deletions are found in 13.2% of GBM, but downregulation of MIG6 expression is observed in 50% of GBM [85]. Therefore, MIG6 deletions cannot account for its frequent downregulation.…”

“…MIG6 expression downregulation and recurrent genetic deletions of its locus on chromosome 1p36 are common events in multiple tumor types [85]. 1p36 deletions are found in 13.2% of GBM, but downregulation of MIG6 expression is observed in 50% of GBM [85].…”

“…EGFR turnover is critical for the regulation of EGFR expression and activity. MIG6, which I discovered as a direct target of miR-148a, is a negative regulator of EGFR expression and activation [85].…”

“…(MIG6) regulates EGFR signaling and turnover by binding EGFR and directly inhibiting tyrosine kinase activity, increasing clathrin-dependent EGFR endocytosis and trafficking into the lysosome, and promoting EGFR degradation [85,98,101]. Ablation of MIG6 induces tumor formation, supporting a tumor suppressor function of MIG6 [85,217].…”

“…Ablation of MIG6 induces tumor formation, supporting a tumor suppressor function of MIG6 [85,217]. The MIG6 gene is located on chromosome 1p36, which is subject to focal deletions in GBM.…”