(Erythroblastic Leukemia Viral Oncogene Homolog) or EGF (Epidermal Growth Factor) family of transmembrane PTKs (Receptor Tyrosine Kinases) plays an important role during the growth and development of a number of organs including the heart, the mammary gland, and the central nervous system. In addition, ErbB
overexpression is associated with tumorigenesis of the breast, ovaries, brain, and prostate gland. The ErbB family includes four members, EGFR (EGF Receptor)/ErbB1/Her1 (Heregulin-1), ErbB2/Her2 (Heregulin-2), ErbB3/Her3 (Heregulin-3), and 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 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 heterodimers 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 EGFR and PDGFR
(Platelet-Derived Growth Factor receptors) (Ref.6).
Ligand binding to the ErbB1 receptor rapidly induces receptor-mediated endocytosis through clathrin-coated pits, and the internalized complexes are subsequently degraded in lysosomes. In contrast to the ErbB1, all other ErbB family members, including ErbB4, are not rapidly internalized in the presence of ligand. Activation-induced endocytosis and downregulation are important in limiting the duration of receptor activation, but their efficiency is low for all members of the ErbB family with the exception of ErbB1. This is probably due to impaired coupling of Cbl, a protein thought to be involved in activation-induced degradation, to ErbB2, ErbB3 and ErbB4.
Ligand-induced formation of the ErbB2-ErbB3 heterodimer at the cell surface leads to activation of several major pathways of signal transduction including ERK2 (Extracellular Signal Regulated Kinase) and Akt
activation by the Ras
pathway leads to cell proliferation through the activation of a number of nuclear targets, including Elk1, PEA3, Sp1, Activating Protein-1, and the c-Myc oncoprotein, which is a major transcription factor and regulator of cell cycle progression. Another pathway is the PI3K-Akt pathway, activation of which results in enhanced antiapoptotic and prosurvival signals, through inhibition of the proapoptotic proteins BAD (BCL2 Associated Death Promoter), GSK3
(Glycogen Synthase Kinase-3), and the transcription factor FKHR-L1 (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 ErbB2-ErbB3 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.