Upon dimerization the tyrosine kinase domains of EGFR and related receptors are activated, bringing about phosphorylation of the hydroxyl group of specific tyrosines on the cytoplasmic tail. This creates binding sites for specific signaling molecules which initiate further intracellular signaling events, as shown in Figure 1. Four possible pathways are shown; the one (or more) which is activated depends upon the dimer partners and the activating ligands. Each of the four pathways, generated by binding and activating phospholipase C, p85/phosphatidylinositol-3-kinase, SHC, or STAT, ultimately leads to changes in the expression of genes involved in the fundamental processes of cell growth, division, and survival.
Fig2. EGFR family signaling pathways. Four intracellular signaling pathways can be initiated by a homo- or heterodimer of the EGFR/HER receptor family. The first step in each is the tyrosine kinase mediated phosphorylation of a protein that generates a second intracellular signal. For example, the phosphorylation of phospholipase C (PLCγ) leads to the release of inositol triphosphate (IP3) and diacylglycerol (DAG), leading to the activation of protein kinase C (PKC). Phosphorylation of p85 activates phosphatidylinositol-3-kinase (PI3K) leading to the activation of Akt (also known as protein kinase B, PKB). The STAT (signal transducer and activator of transcription) pathway and the MAP kinase pathway are also activated by the receptor tyrosine kinase activity as shown. Depending on the pathway(s) activated, the cell type, and its environment (e.g., exposure to other signaling inputs) these pathways, alone or in combination, will lead to changes in gene expression which will influence the ability of the cell to divide, differentiate, undergo, or resist apoptosis and survive. GRB2, growth factor receptor bound-2, an adaptor protein; SOS, son of sevenless guanine nucleotide exchange protein.
Usually the result of EGF/HER receptor activation is the normal growth and differentiation of specific tissues. For example, EGF and TGFα are critical participants in the normal development of the skin, lung, intestine, eye, and mammary gland. However, if there is overexpression or mutation of the receptor proteins, the expression of genes controlling cell proliferation and differentiation can be altered such that the rate of growth escapes the normal controls. For example, the inappropriate overexpression of one of the receptor proteins is linked to several forms of cancer. This is especially true of the favored dimerization partner, HER2, which can become activated in the absence of a ligand and has become an important target of cancer chemotherapy.
The normal physiological functions are known for only some of the EGF/HER receptor ligands listed in Table 1. For example, amphiregulin is mitogenic for a range of targets including astrocytes, Schwann cells, and fibroblasts. Betacellulin is a potent mitogen for retinal pigment epithelial cells and neuregulin 1 stimulates the expression of the acetylcholine receptor in the cells of synaptic nuclei.
Table1. Members of the EGF Family
