Signaling of Epidermal Growth Factor Receptor Family and Its Implications in Cancers

Dear Colleagues,

The epidermal growth factor receptor (EGFR), like other receptor tyrosine kinases (RTKs), regulates key events in cell growth, differentiation, survival and migration. Aberrant signaling from EGFR has been implicated in many diseases. EGFR is historically the prototypical RTK. It was the first of this large family of transmembrane receptors to be cloned, and the first for which a clear connection between aberrant receptor function and cancer could be drawn.

There are four members in the ErbB receptor family, also known as the EGFR family or type I receptor family, including EGFR or ErbB1/Her1, ErbB2/Her2, ErbB3/Her3 and ErbB4/Her4. The ErbB receptor family is unique among various groups of RTKs in that ErbB3 has impaired kinase activity, while ErbB2 does not have a direct ligand. Therefore, heterodimerization is an important mechanism that allows the activation of all ErbB receptors in response to ligand stimulation. The activated ErbB receptors bind to many signaling proteins and stimulates the activation of many signaling pathways, including the Ras-Raf-Mek-ERK, PI3K-Akt-Tor, PLC-γ1, STAT and Src pathways. The specificity and potency of intracellular signaling pathways are determined by positive and negative regulators, the specific composition of activating ligand(s), receptor dimer components, and the diverse range of proteins that associate with the tyrosine phosphorylated C-terminal domain of the ErbB receptors. Through the control of these diverse signaling networks, ErbB receptors regulate many critical cellular processes, such as cell proliferation, cell differentiation, cell survival, cell metabolism, cell migration, and cell cycle. Binding of EGF to EGFR also stimulates the rapid internalization of EGFR. EGFR endocytosis and EGFR-mediated cell signaling are mutually regulated.

EGFR and ErbB2 have been implicated in the development of many types of human cancer. Genetic changes that have been detected in human tumors include gene amplification leading to receptor overexpression, activating kinase domain mutations mainly in EGFR but also in ErbB2, in-frame deletions in the extracellular domain of EGFR (EGFR vIII), and coexpression of ErbB ligands and receptors in tumors. Each alteration promotes constitutive receptor activation, a process that stimulates cancer development. Dysregulation of the EGFR signaling cascade due to overexpression or constitutively activating mutations is well-established in many cancer types, including breast, lung, colorectal, esophageal, head and neck, esophageal, and anal cancer, as well as glioma and glioblastoma. ErbB2 overexpression or ERBB2 gene amplification occurs in 20–30% of breast cancers and ovarian cancers. Moreover, approximately 1.6% of breast cancer patients possess an ERBB2 mutation. Various monoclonal antibodies targeting EGFR and ERBB2 have either been approved or are in clinical trials for treating different types of cancers.

In spite of significant advances in our understanding of EGFR signaling and trafficking, some critical knowledge is still lacking. Novel signaling pathways and cell functions are continuously identified to be regulated by the EGFR family. EGFR family receptors are still intensively explored for the development of novel therapies targeting various cancers. This Special Issue will cover the recent progress in all of the areas related to EGFR family signaling and cancer.

Prof. Dr. Zhixiang Wang
Guest Editor

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• EGFR
• ErbB receptor
• cell signaling
• trafficking
• cell cycle
• cancer
• targeted cancer therapy