Ying, H. Q., Zheng, H. W., Scott, K., Wiedemeyer, R., Yan, H. Y., Lim, C., Huang, J., Dhakal, S., Ivanova, E., Xiao, Y. H., Zhang, H. L., Hu, J., Stommel, J. M., Lee, M. A., Chen, A. J., Paik, J. H., Segatto, O., Brennan, C., Elferink, L. A., Wang, Y. A., Chin, L., DePinho, R. A. (April 2010) Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proceedings of the National Academy of Sciences of the United States of America, 107 (15). pp. 6912-6917. ISSN 0027-8424
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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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | glioblastoma vesicle STX8 TUMOR-SUPPRESSOR GLIOBLASTOMA-MULTIFORME SYNTAXIN 8 CANCER GENE 1P ASSOCIATION PROGRESSION EXPRESSION RECEPTOR Multidisciplinary Sciences |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR diseases & disorders > cancer > cancer types > glioblastoma |
| CSHL Authors: | |
| Communities: | CSHL labs > Zheng lab |
| Depositing User: | Matt Covey |
| Date: | April 2010 |
| Date Deposited: | 22 Aug 2014 18:58 |
| Last Modified: | 22 Aug 2014 18:58 |
| PMCID: | PMC2872443 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30701 |
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