Figure 1 shows the four distinct receptor protomers for the members of the EGF family of growth factors. The nomenclature is shown beneath the protomers: EGFR, which binds EGF, TGFα, and amphiregulin; HER2, for which no ligand has been identified; HER3 which binds neuregulins 1 and 2; and HER4, which binds neuregulins 3 and 4, as well as 1 and 2. In addition, both EGFR and HER4 bind betacellulin, heparin-binding EGF, and epiregulin. Because of its role in the control of cell growth, the EGF receptor is a proto-oncogene and in this context it is known as c-ErbB1 or ErbB1. The three related receptors then, in addition to their HER (human epidermal growth factor receptor) designations, are also known as ErbB2, ErbB3, or ErbB4.
Fig1. Structural features of the EGFR and related receptors. The four receptor tyrosine kinases that make up this family are shown in their protomeric forms on the left side of the figure. Above each are the ligands which bind with high affinity. From left to right the protomers are known as: EGFR (ErbB-1); HER2 (neu/ErbB-2); HER3 (ErbB-3); and HER4 (ErbB-4). These receptors are single membrane spanning receptor tyrosine kinases. Both heterodimers and homodimers can form and an example of each is shown on the right side of the figure. Each of the protomers has four extracellular domains which, upon binding ligand, change conformation, exposing a dimerization face. HER2 has no known ligands and is in the conformation exposing the dimerization face in the absence of a ligand. The intracellular portion of each of the four protomers contains a tyrosine kinase (TK). The TK of HER3 is inactive. When heterodimers form, TK is activated, bringing about autophosphorylation and phosphorylation of adjacent proteins to initiate signaling cascades (see Figure 2). HER3 is thought to be phosphorylated by its dimerization partner, HER2, in the figure. See Table 1 for definition of ligand abbreviations.
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.
Table1. Members of the EGF Family
Each of the four EGF receptor protomers consists of a cytoplasmic (carboxy terminal) portion containing a tyrosine kinase domain, a single pass membrane- spanning region, and an N-terminal extracellular portion consisting of four distinct domains, one of which is the dimerization domain. In EGFR, HER3 and HER4, ligand binding induces a conformational change that brings about dimerization. HER2, with no known ligand, is always in the dimerization conformation and can therefore, in the absence of ligand, form a heterodimer with any of the other protomers. Although heterodimers can form between any of the receptor protomers, HER2 is the preferred heterodimerization partner for the others. EGFR, HER3 and HER4 can all form homodimers in the presence of ligand, but HER2 does not form homodimers. The tyrosine kinase domain of HER3 is nonfunctional, but the receptor can be phosphorylated by a heterodimerization partner.
