LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

Abstract

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( þ ) 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.

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

“…Ectopically expressed LRIG1 also affects the basal rate of EGFR degradation (Laederich et al, 2004), although it is unclear whether this requires ubiquitylation of surfaceexposed EGFR molecules. In fact, expression of the dominantnegative CBL-70Z allele, which encodes a mutant form of the enzyme that is unable to direct ubiquitylation of CBL targets, did not prevent ectopic LRIG1 from reducing EGFR expression in the absence of EGF stimulation (Stutz et al, 2008). In summary, the available evidence suggests that LRIG1 overexpression accelerates basal, as well as ligand-induced, EGFR degradation.…”

“…Although these studies did not correlate LRIG1 expression with that of EGFR, it is intriguing that LRIG1 regulates stem cell quiescence in a prototypical squamous epithelium, such as the epidermis (Jensen and Watt, 2006;Jensen et al, 2009), and that overexpression of EGFR and its ligands might be involved in the pathogenesis of HNSCCs (Morgan and Grandis, 2009). A role for LRIG1 has been proposed in the suppression of EGFRvIII oncogenic signals in GBM cells (Stutz et al, 2008), but it is still unknown whether and how frequently LRIG1 loss occurs during GBM progression. It is interesting, however, that LRIG1, unlike RALT, is capable of targeting EGFRvIII for degradation (Stutz et al, 2008).…”

“…A role for LRIG1 has been proposed in the suppression of EGFRvIII oncogenic signals in GBM cells (Stutz et al, 2008), but it is still unknown whether and how frequently LRIG1 loss occurs during GBM progression. It is interesting, however, that LRIG1, unlike RALT, is capable of targeting EGFRvIII for degradation (Stutz et al, 2008).…”

The shaping of invasive glioma phenotype by the ubiquitin–proteasome system

“…Particularly for EGFR signaling pathway, mutant EGFRvIII induces a specifi c pattern of genes with pronounced roles in enhancement of invasion, such as ECM proteins, metalloproteases and a serine protease (Lal et al, 2002). In EGFRvIII-expressing GBM cells, loss of the EGFRvIII negative regulator, LRIG1, which targets EGFRvIII for proteasome degradation, contributes to increased motility and invasion (Stutz et al, 2008).…”

EGFR as a therapeutic target in glioblastoma

“…4 -PI3K catalyzes PIP 3 formation from PIP 2 . 5 -PIP 3 promotes Akt activation and downstream anti-apoptotic pathways on potential EGFR downregulators, such as the leucine-rich repeats and immunoglobulin-like domain (LRIG) family of proteins, which may also be of therapeutic interest [19]. Finally, both parallel pathways and downstream components of the EGFR pathways are important to consider when analyzing the efficacy of EGFR-targeted therapies [20][21][22][23].…”