HER/ErbB Family

The epidermal growth factor (EGF) receptor is a transmembrane tyrosine kinase that belongs to the HER/ErbB protein family. Ligand binding results in receptor dimerization, autophosphorylation, activation of downstream signaling, internalization, and lysosomal degradation. The GRB2 adaptor protein binds activated EGFR at phospho-Tyr1068. 

The ErbB2 (HER2) proto-oncogene encodes a 185 kDa transmembrane, receptor-like glycoprotein with intrinsic tyrosine kinase activity. While ErbB2 lacks an identified ligand, ErbB2 kinase activity can be activated in the absence of a ligand when overexpressed and through heteromeric associations with other ErbB family members. Amplification of the ErbB2 gene and overexpression of its product are detected in almost 40% of human breast cancers. The major autophosphorylation sites in ErbB2 are Tyr1248 and Tyr1221/1222; phosphorylation of these sites couples ErbB2 to the Ras-Raf-MAP kinase signal transduction pathway. 

 HER3/ErbB3 is a member of the ErbB receptor protein tyrosine kinase family, but lacks tyrosine kinase activity. Tyrosine phosphorylation of ErbB3 depends on its association with other ErbB tyrosine kinases. Upon ligand binding, heterodimers form between ErbB3 and other ErbB proteins, and ErbB3 is phosphorylated on tyrosine residues by the activated ErbB kinase. There are at least 9 potential tyrosine phosphorylation sites in the carboxy-terminal tail of ErbB3. These sites serve as consensus binding sites for signal transducing proteins, including Src family members, GRB2, and the p85 subunit of PI3 kinase, which mediate ErbB-downstream signaling. Both Tyr1222 and Tyr1289 of ErbB3 reside within a YXXM motif and participate in signaling to PI3 kinase. 

 HER4/ErbB4, like other family members, has four ectodomains, a single transmembrane domain, and a cytoplasmic tail containing the active tyrosine kinase domai. By binding to neuregulins and/or EGF family ligands, ErbB4 forms either a homodimer or heterodimer with other ErbB family members, which results in receptor activation and signaling. ErbB4 is ubiquitously expressed with the highest expression occurring in the brain and heart. The expression of ErbB4 in breast cancer, pediatric brain cancer, and other types of carcinomas has been reported, suggesting that ErbB4 expression is involved in both normal tissue development and carcinogenesis.