Associate editor: J. SiegfriedSignaling through the epidermal growth factor receptor during the development of malignancy
Introduction
Transformation of fibroblasts by constitutively activated growth factor receptors, such as the epidermal growth factor receptor (EGFR), implicates EGFR signaling in carcinogenesis. The EGFR is a receptor tyrosine kinase that is overexpressed in a variety of human epithelial malignancies, including carcinomas of the lung, colon, ovary, bladder, and head and neck (Salomon, 1995). Mutated forms of EGFR have been identified in selected cancers where ligand-independent signaling contributes to tumor progression. EGFR stimulation mediates several properties that are critical for tumor formation and progression, including proliferation, cell motility, cell adhesion, invasion, cell survival, and angiogenesis. Autocrine or paracrine stimulation of signaling pathways through the EGFR mediates these tumorigenic functions, sometimes in a pathway-specific manner. This review will examine these signaling pathways and discuss their importance in carcinogenesis.
Section snippets
Physiologic role of epidermal growth factor receptor family tyrosine kinases
The EGFR is a 170-kDa plasma membrane glycoprotein containing an extracellular ligand-binding domain, a single transmembrane region, an intracellular domain with intrinsic tyrosine kinase activity, and a C-terminal tail that contains specific tyrosine containing sequences that become binding sites for SH2-containing signaling proteins upon phosphorylation. The EGFR is one of a family of 4 structurally similar receptors (ErbB family) that demonstrate homology in their kinase domains, but diverge
Metazoan conservation of the epidermal growth factor receptor
The importance of EGFR in basic biologic functions is reflected by the conservation of this growth factor receptor in many other organisms. In general, the size of the receptor as well as the extracellular/transmembrane/cytoplasmic domain structure has been maintained. The let-23 gene encodes a tyrosine kinase of the EGFR subfamily that is necessary for induction of the Caenorhabditis elegans vulva (Aroian et al., 1990). A single member of the EGFR tyrosine kinase family is present in the
The epidermal growth factor receptor signaling network
The ErbB family of receptors can undergo homo- or heterodimerization both constitutively and in response to ligands, thus resulting in tremendous signaling diversity (Fig. 1). EGFR/ErbB1 has several ligands that bind exclusively to the EGFR, including epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), and amphiregulin. No ligand has yet been identified that binds to the second member of the ErbB family, ErbB2/Her2-neu. This receptor appears to be activated by
Pathological basis of epidermal growth factor receptor signaling during carcinogenesis
Overexpression of EGFR and its ligands, primarily TGF-α, has been detected in premalignant lesions, thus implicating this autocrine pathway in the early stages of tumor formation. Specifically, EGFR has been found to be up-regulated in oral dysplasias compared with levels in normal mucosa Rubin Grandis et al., 1998a, Rubin Grandis et al., 1998b, Srinivasan & Jewell, 2001, Bankfalvi et al., 2002. The mechanism of EGFR overexpression has been attributed to both transcriptional activation and gene
Signaling through mutant epidermal growth factor receptor in cancer
The most common mutation of the EGFR in human cancers appears to be a deletion of part of the extracellular domain that yields a constitutively active receptor that engages in ligand-independent signaling (Fig. 2). This mutation was originally identified in gliomas where it correlated with enhanced pathogenicity and chemotherapeutic resistance. Known as EGFRvIII, this 145-kDa mutant is expressed exclusively in cancer cells where it activates classic oncogenic signaling pathways Prigent et al.,
Conclusion
The EGFR is highly conserved in development and has been shown to regulate a variety of important functions in normal mammalian epithelial cells, including growth, survival, differentiation, and morphogenesis. A proto-oncogene, EGFR can induce transformation and is overexpressed in a broad array of malignancies. Although gene amplification has been reported in cancer cell lines, epigenetic causes appear to account for most cases of overexpression. Increased levels of EGFR and overproduction of
Acknowledgements
This work was supported by NIH grant CA77308 (to J.R.G.).
References (90)
- et al.
Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor
J Biol Chem
(1998) - et al.
The expression of type I growth factor receptors in the squamous neoplastic changes of uterine cervix
Gynecol Oncol
(1999) Epidermal growth factor receptor as a therapeutic target in colorectal cancer
Clin Colorectal Cancer
(2003)- et al.
Epidermal growth factor receptor family in lung cancer and premalignancy
Semin Oncol
(2002) - et al.
A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer
Eur J Cancer
(1996) - et al.
Epidermal growth factor receptors as a target for cancer treatment: The emerging role of IMC-C225 in the treatment of lung and head and neck cancers
Semin Oncol
(2002) - et al.
Binding specificities and affinities of egf domains for ErbB receptors
FEBS Lett
(1999) - et al.
The localization of transforming growth factor alpha and epidermal growth factor receptor in stromal and epithelial compartments of developing human prostate and hyperplastic, dysplastic, and carcinomatous lesions
Hum Pathol
(1998) - et al.
Overexpression of phospholipase C-gamma 1 in colorectal carcinomas is associated with overexpression of factors that bind its promoter
J Biol Chem
(1995) - et al.
Transactivation of the epidermal growth factor receptor in colonic epithelial cells by carbachol requires extracellular release of transforming growth factor-alpha
J Biol Chem
(2002)