The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

Abstract

The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) for which ligand binding was studied and for which the importance of ligand-induced dimerization was established. As a result, EGFR and its relatives have frequently been termed "prototypical" RTKs. Many years of mechanistic studies, however, have revealed that-far from being prototypical-the EGFR family is quite unique. As we discuss in this review, the EGFR family uses a distinctive "receptor-mediated" dimerization mechanism, with ligand binding inducing a dramatic conformational change that exposes a dimerization arm. Intracellular kinase domain regulation in this family is also unique, being driven by allosteric changes induced by asymmetric dimer formation rather than the more typical activationloop phosphorylation. EGFR family members also distinguish themselves from other RTKs in having an intracellular juxtamembrane (JM) domain that activates (rather than autoinhibits) the receptor and a very large carboxy-terminal tail that contains autophosphorylation sites and serves an autoregulatory function. We discuss recent advances in mechanistic aspects of all of these components of EGFR family members, attempting to integrate them into a view of how RTKs in this important class are regulated at the cell surface.

The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling

“…The epidermal growth factor receptor (EGFR 2 ; HER1; ErbB1) is the principal member of the human ErbB receptortyrosine kinase family that facilitates diverse signal transduction pathways to regulate imperative cellular functions including growth, development, differentiation, and migration (1). A transmembrane protein expressed on the cell membrane, EGFR consists of an extracellular ligand binding domain, a single transmembrane-spanning sequence, and an intracellular kinase domain containing a C-terminal peptide tail with several tyrosine residues targeted for autophosphorylation or phosphorylation by related tyrosine kinases (2).…”

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

“…It is well reported that the activation of EGF and its cognate receptor, EGFR, can modulate cell proliferation, survival, invasion and metastasis through activating the autophosphorylation of EGFR and stimulating PI3K/AKT and MAPKs signaling (2,3). In the present study, the effects of tetrandrine on the activation (tyrosine phosphorylation) of EGFR were examined in EGF-induced HT29 cells.…”

“…Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (1), and EGFR activation by ligand binding stimulates multiple signals, including phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB pathways, ultimately resulting in cellular proliferation, survival, angiogenesis invasion and metastasis (2,3). Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13).…”

HER2 Pro1170Ala polymorphism is associated with decreased survival rate in HER2-negative breast cancer

“…Located on chromosome 17q21, it codes for a transmembrane glycoprotein with tyrosine kinase activity (3). HER2 is markedly homologous with EGFR, which serves an important role in the regulation of cell growth, differentiation and invasion (2,3). It is well documented that HER2 amplification and/or overexpression is associated with a worse clinical outcome in breast cancer (4)(5)(6)(7)(8)(9).…”

“…The human epidermal growth factor receptor 2 (HER2) gene (also known as erbB-2 or neu) is a member of the epidermal growth factor receptor (EGFR) family (1,2). Located on chromosome 17q21, it codes for a transmembrane glycoprotein with tyrosine kinase activity (3).…”