The EGFR/ERBB receptor family

In metazoa, inductive cell-to-cell interactions play crucial roles, both in embryonic development and in homeostasis. Many such interactions are mediated by RTKs and their soluble or surface-bound ligand growth factors. Type 1 RTKs, also called the ERBB or HER family, comprises four proteins, which bind growth factors of the EGF and neuregulin families. The four ERBB/HER proteins are crucial not only for the determination of several epithelial, glial, muscle, and neuronal lineages, but they are also key players in pathological processes, such as malignant transformation. Multiple mechanisms underlay the driver or supportive functions of ERBB/HER proteins in tumors, and they include receptor overexpression, receptor’s point mutations, and internal deletions, as well as autocrine loops, meaning that a cell initiates its own proliferation through ligand secretion. Although all ERBB/HER receptors share similar domain architecture, ERBB2/HER2 binds with no known ligand and ERBB3/HER3 harbors a barely active kinase domain. Like other RTKs, ERBB/HER proteins signal downstream through the ERK/MAPK and PI3K/AKT pathways. However, ERBB/HER proteins are characterized by extensive receptor-receptor interactions, with ERBB2/HER2 functioning as a preferred heterodimer partner. In recent years, the ability of ERBB/HER proteins to redirect signals by means of network plasticity is emerging as an important way developed by tumors to evade pharmacological interceptors aimed at specific nodes of the network.