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. 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.
Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas.
Gao
G
Guo
Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas.
Ke
K
Gong
Department of Neurosurgery, The University of Texas Southwestern Medical Center, Dallas, Texas. VA North Texas Health Care System, Dallas, Texas.
Bryan
B
Wohlfeld
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Kimmo J
KJ
Hatanpaa
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Dawen
D
Zhao
Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas. VA North Texas Health Care System, Dallas, Texas. Amyn.Habib@UTSouthwestern.edu.
Amyn A
AA
Habib
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics*
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008024:Ligands; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt