Mig-6 controls EGFR trafficking and suppresses gliomagenesis Journal Article
| Authors: | 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.; Wang, Y. A.; Chin, L.; DePinho, R. A. |
| Article Title: | 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. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; gene deletion; glioma; brain neoplasms; protein function; cell proliferation; animals; mice; embryo; protein degradation; protein depletion; epidermal growth factor receptor; protein binding; receptor, epidermal growth factor; cell line, tumor; carcinogenesis; tumor suppressor gene; gene expression regulation, neoplastic; glioblastoma; tumor suppressor proteins; tumor cell; adaptor proteins, signal transducing; genomics; neoplasm invasiveness; tumor suppressor protein; cell adhesion; lysosome; lysosomes; two-hybrid system techniques; endosome; stx8; vesicle; protein mig 6; snare protein; syntaxin; syntaxin 8; gliomagenesis |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 15 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-04-13 |
| Start Page: | 6912 |
| End Page: | 6917 |
| Language: | English |
| DOI: | 10.1073/pnas.0914930107 |
| PUBMED: | 20351267 |
| PROVIDER: | scopus |
| PMCID: | PMC2872443 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
