Mig-6 controls EGFR trafficking and suppresses gliomagenesis.
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.
Ying
Haoqiang
H
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Zheng
Hongwu
H
Scott
Kenneth
K
Wiedemeyer
Ruprecht
R
Yan
Haiyan
H
Lim
Carol
C
Huang
Joseph
J
Dhakal
Sabin
S
Ivanova
Elena
E
Xiao
Yonghong
Y
Zhang
Hailei
H
Hu
Jian
J
Stommel
Jayne M
JM
Lee
Michelle A
MA
Chen
An-Jou
AJ
Paik
Ji-Hye
JH
Segatto
Oreste
O
Brennan
Cameron
C
Elferink
Lisa A
LA
Wang
Y Alan
YA
Chin
Lynda
L
DePinho
Ronald A
RA
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
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