ErbB Signaling

The ErbB or EGF family of transmembrane RTKs plays an important role during growth and development of a number of tissues including the heart, mammary gland and the central nervous system. The ErbB family includes four members: EGFR/ErbB1/Her1, ErbB2/Her2, ErbB3/Her3, and ErbB4/Her4. ErbBs consist of an extracellular ligand-binding domain, a single membrane-spanning region and a cytoplasmic protein tyrosine kinase domain. Although these receptors share common structural elements, 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. 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 and TGF-α, which bind specifically to ErbB1; the second group comprises of Btc, HBEGF and Ereg and exhibit dual specificity for ErbB1 and ErbB4. The third group is composed of the NRGs and form two subgroups based upon their capacity to bind ErbB3 and ErbB4 (NRG1 and NRG2) or only ErbB4 (NRG3 and NRG4).Ligand binding to ErbB receptors induces formation of homo- or heterodimer receptor complexes leading to activation of the intrinsic kinase domain and subsequent phosphorylation on specific tyrosine residues within the cytoplasmic tail. These phospho-tyrosine residues provide docking sites for SH2 and PTB domain containing proteins which include PI3K, PLC-γ and SHC. This leads to activation of the Ras/Raf/MEK/ERK and PI3k/AKT signaling pathways, the former leading to cell proliferation while the latter results in enhanced anti-apoptotic signals. Depending on the specific cell context, activation of the ErbB receptors may promote proliferation, motility, adhesion, differentiation or even apoptosis.