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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Scott
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Wiedemeyer
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yan
authors.forename: Carol
authors.initials: C
authors.lastname: Lim
authors.forename: Joseph
authors.initials: J
authors.lastname: Huang
authors.forename: Sabin
authors.initials: S
authors.lastname: Dhakal
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Jayne M
authors.initials: JM
authors.lastname: Stommel
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lee
authors.forename: An-Jou
authors.initials: AJ
authors.lastname: Chen
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Oreste
authors.initials: O
authors.lastname: Segatto
authors.forename: Cameron
authors.initials: C
authors.lastname: Brennan
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Elferink
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors