Mig-6 controls EGFR trafficking and suppresses gliomagenesis

Haoqiang Ying, Hongwu Zheng, Kenneth Scott, Ruprecht Wiedemeyer, Haiyan Yan, Carol Lim, Joseph Huang, Sabin Dhakal, Elena Ivanova, Yonghong Xiao, Hailei Zhang, Jian Hu, Jayne M. Stommel, Michelle A. Lee, An Jou Chen, Ji Hye Paik, Oreste Segatto, Cameron Brennan, Lisa A. Elferink, Y. Alan WangLynda Chin, Ronald A. DePinho

Research output: Contribution to journalArticle

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6912-6917
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number15
DOIs
StatePublished - Apr 13 2010
Externally publishedYes

Keywords

  • Glioblastoma
  • STX8
  • Vesicle

ASJC Scopus subject areas

  • General

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  • Cite this

    Ying, H., Zheng, H., Scott, K., Wiedemeyer, R., Yan, H., Lim, C., Huang, J., Dhakal, S., Ivanova, E., Xiao, Y., Zhang, H., Hu, J., Stommel, J. M., Lee, M. A., Chen, A. J., Paik, J. H., Segatto, O., Brennan, C., Elferink, L. A., ... DePinho, R. A. (2010). Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 6912-6917. https://doi.org/10.1073/pnas.0914930107