Epidermal growth factor receptor kinase domain, Human epidermal growth factor receptor 2 kinase domain, Human epidermal growth factor receptor 4 kinase domain (EGFR kinase domain, HER2 kinase domain, HER4 kinase domain)

EGFR, HER2, and HER4 kinase domains are intracellular portions of transmembrane receptor tyrosine kinases of the ErbB family. Upon ligand binding and receptor dimerization, these kinase domains become activated by allosteric mechanisms, resulting in trans-autophosphorylation. This phosphorylation recruits downstream effectors that mediate cell proliferation, survival, and differentiation. Aberrant activation, due either to overexpression, mutation, or ligand-independent activity, is implicated in the pathogenesis of multiple cancers. Therapeutics targeting these kinase domains employ small molecule inhibitors or monoclonal antibodies to block kinase activity or receptor dimerization. Although EGFR and HER2 are extensively targeted in clinical oncology, HER4 targeting is less common. These kinases share structural and mechanistic features, including dimerization-dependent activation, but also possess unique biochemical properties. Their inhibition can result in significant side effects given their roles in growth and tissue maintenance.

Other names

EGFR kinaseHER2 kinaseHER4 kinaseErbB1 kinaseErbB2 kinaseErbB4 kinaseEpidermal growth factor receptor family kinases

Inhibition of kinase activity (ATP competitive); Disruption of dimerization/activation; Blocking ligand binding; Inducing receptor internalization and degradation