Ligand-Independent EGFR Signaling

Constitutive activation of the EGFR is common in cancer due to EGFR wild-type (EGFRwt) overexpression or the presence of mutant EGFR. Signaling by constitutively active NSCLC EGFR mutants or the EGFRvIII mutant in glioblastoma has been studied intensively and the downstream signals are known. Normal...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-09, Vol.75 (17), p.3436-3441
Main Authors: Guo, Gao, Gong, Ke, Wohlfeld, Bryan, Hatanpaa, Kimmo J, Zhao, Dawen, Habib, Amyn A
Format: Article
Language:English
Subjects:
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Gene Expression Regulation, Neoplastic
Humans
Interferon Regulatory Factor-3 - genetics
Ligands
MAP Kinase Signaling System - genetics
Mutation
Proto-Oncogene Proteins c-akt
Receptor, Epidermal Growth Factor - biosynthesis
Receptor, Epidermal Growth Factor - genetics
Signal Transduction - genetics
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Summary:Constitutive activation of the EGFR is common in cancer due to EGFR wild-type (EGFRwt) overexpression or the presence of mutant EGFR. Signaling by constitutively active NSCLC EGFR mutants or the EGFRvIII mutant in glioblastoma has been studied intensively and the downstream signals are known. Normally, the EGFRwt is activated when it is exposed to ligand, resulting in activation of canonical signals such as ERK and Akt. The EGFRwt also becomes tyrosine phosphorylated and constitutively activated without ligand when it is overexpressed, but downstream signals are unclear. Recent studies have identified a noncanonical form of signaling triggered by EGFRwt exclusively in the absence of ligand that does not involve ERK or Akt activation but, instead, results in activation of the transcription factor IRF3. The addition of ligand turns off IRF3-dependent transcription and activates ERK and Akt. Thus, the EGFR triggers distinct and mutually exclusive signaling networks, depending on the presence of ligand. Furthermore, noncanonical EGFRwt signaling may influence response to treatment in cancer. Also, there are reports of both synergistic and antagonistic interactions between ligand-dependent EGFRwt and EGFRvIII signaling. Here, we discuss ligand-independent EGFR signal transduction by oncogenic EGFR mutants and EGFRwt, and review the interplay between EGFRwt and EGFRvIII.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-0989