ErbB Family Pathway

• EGFR (EGF Receptor)/ErbB1/Her1 (Heregulin-1)
• ErbB2/Her2 (Heregulin-2)
• ErbB3/Her3 (Heregulin-3)
• ErbB4/Her4 (Heregulin-4) (Ref. 1)

Two of the family members, ErbB1 and ErbB2, are involved in the development of many types of human cancer. All ErbBs have in common an extracellular ligand-binding domain, a single membrane-spanning region, and a cytoplasmic protein tyrosine kinase domain (Ref. 2). Although these receptors share common structural elements, including an extracellular ligand-binding domain and an intracellular tyrosine kinase domain, ligands have been identified only for ErbB1, ErbB3, and ErbB4. ErbB2 remains an orphan receptor, with no diffusible ErbB2-specific ligand identified. However, ErbB2 can be transactivated through heterodimerization with other ErbB family members and appears to be their preferred heterodimerization partner.

Under normal physiological conditions, activation of the ErbB receptors is controlled by spatial and temporal expression of their ligands, members of the EGF-related peptide growth factor family. There are at least 16 different EGF family ligands that bind ErbB receptors. The ligands can be grouped into three categories.

• The first group includes EGF, Areg (Amphiregulin), and TGF-Alpha (Transforming Growth Factor-Alpha), which bind specifically to ErbB1.
• The second group includes Btc (Betacellulin), HBEGF (Heparin-Binding EGF), and Ereg (Epiregulin), which exhibit dual specificity in that they bind ErbB1 and ErbB4.
• The third group is composed of the Nrg (Neuregulins) and forms two subgroups based upon their capacity to bind ErbB3 and ErbB4 (Nrg1 and Nrg2) or only ErbB4 (Nrg3 and Nrg4) (Ref. 3). ErbB2 can be recruited by IL-6 (Interleukin-6) to the GP130 subunit of the IL-6 receptor complex to facilitate signal transduction.

Ligand binding to ErbB receptors induces formation of homo- and heterodimer receptor complexes, leading to activation of the intrinsic kinase domain and subsequent phosphorylation on specific tyrosine residues within the cytoplasmic tail (Ref. 4).These phosphorylated tyrosines provide docking sites for SH2 (Src Homology-2) and PTB (Phosphotyrosine Binding) domain-containing proteins, which include p85 subunit of PI3K (Phosphoinositide-3 Kinase), PLC-Gamma (Phospholipase-C-Gamma), Src family kinases, protein tyrosine phosphatases, SH2 domain-containing tyrosine phosphatases 1 and 2, SHC and GRB2 (Growth Factor Receptor-Bound Protein-2), GRB7 (Growth Factor Receptor-Bound Protein-7), GRB10 (Growth Factor Receptor-Bound Protein-10), c-Cbl, Nck, Crk, EPS8 (EGFR Pathway Substrate-8), and EPS15 (EGFR Pathway Substrate-15). This leads to activation of signaling pathways such as the MAPK (Mitogen-Activated Protein Kinase) pathway and the S6 kinase cascade (Ref. 5).

ErbB receptors also induce tyrosine phosphorylation of proteins involved in cell adhesion signaling such as the FAK (Focal Adhesion Kinase), CAS (Crk-Associated Substrate), paxillin, cortactin, and catenins. It is found that different ErbB dimers recruit or activate different sets of signaling molecules. The p85 subunit of PI3-kinase is found to associate only with ErbB3, c-Cbl with ErbB1, and Crk with ErbB2. c-Src associates with both ErbB1 and ErbB2, though it prefers ErbB2 over ErbB1. c-Cbl promotes the ubiquitination and degradation of activated EGF and PDGF (Platelet-Derived Growth Factor) receptors (Ref. 6).

Following Nrg1 binding, heteromeric ErbB2/3 receptors auto- and trans-phosphorylate specific tyrosine residues, and to these phosphorylated residues specific adaptor proteins and enzymes are recruited. This results in the activation of a number of downstream signaling pathways, including PI3K/Akt, Erk1/2, FAK, and Rac/Cdc42, and Ca2+-regulated pathways downstream of PLC-gamma lead to activation of calcineurin. Shp2 and Src are thought to regulate Erk1/2 signaling by modulating Ras, although other mechanisms also have been observed (Ref. 7). In addition, the PLC-Gamma and the JAK-STAT (Janus Kinase- Signal Transducers and Activators of Transcription Factors) pathways are indicated, with their resulting enhancement of transcription leading to cell proliferation. A major player acting downstream of ErbB-2-ErbB-3 is Cyclin-D1. A number of pathways lead from the receptors to enhanced activation of Cyclin-D1, thereby promoting cell cycle progression. Depending on the specific cell context, activation of the ErbB receptors may promote proliferation, motility to adhesion, differentiation, or even apoptosis (Ref. 8). On aggregate, these interactions may significantly add to, or even alter the response of cells to ligands.