Fig. 1

Role of HER2-targeted drugs in HER signaling. The four HER family receptors share structural homology with a structure comprising extracellular, transmembrane, and intracellular domains. The extracellular region comprised of four subdomains (I–IV) involved in ligand binding and receptor dimerization; the intracellular region was linked to the single-pass, hydrophobic transmembrane domain, comprising of tyrosine-kinase domain and a tail region that contains several sites of tyrosine phosphorylation. Of note, HER2 harbors no ligand-binding cleft and HER3 has defective intracellular kinase domain. HER2 can form homodimers and also heterodimers with HER-1, -3, and -4 in an open active conformation to regulate downstream signaling pathways, notably phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and Ras/mitogen-activated protein kinase (MAPK) pathways