LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII.
Epidermal growth factor receptor (EGFR) mutation is frequently observed in human cancer and contributes to the growth, survival and therapeutic resistance of tumors. EGFRvIII is an oncogenic EGFR mutant resulting from the deletion of exons 2-7 and is the most common EGFR mutant observed in glioblastoma multiforme, an aggressive brain tumor. EGFRvIII is constitutively active but poorly ubiquitinated, leading to inefficient receptor trafficking to lysosomes and unattenuated oncogenic signaling. The mechanism by which EGFRvIII evades downregulation is not fully understood although recent studies suggest that its interaction with the ubiquitin ligase Cbl may be compromised. In this study, we examine the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain. Here, we determine whether the extracellular domain deletion in EGFRvIII renders it refractory to LRIG1 regulation. We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. We demonstrate that LRIG1 regulation of EGFRvIII is distinct from the only other known mechanism of EGFR regulation, Cbl-mediated degradation. Ectopic expression of LRIG1 in EGFRvIII(+) glioblastoma cells opposes EGFRvIII-driven tumor cell proliferation, survival, motility and invasion. Finally, RNAi-mediated silencing of LRIG1 alters EGFRvIII intracellular trafficking and leads to enhanced EGFRvIII expression, suggesting that loss of LRIG1 in tumors may contribute to a permissive environment for EGFRvIII overexpression, contributing to EGFRvIII oncogenesis.
Basic Sciences, UC Davis Cancer Center, Sacramento, CA 95817, USA.
M A
MA
Stutz
D L
DL
Shattuck
M B
MB
Laederich
K L
KL
Carraway
C
C
Sweeney
D017209:Apoptosis; D066246:ErbB Receptors / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology
C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; C410723:epidermal growth factor receptor VIII; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; C067419:CBL protein, human