ERBB3

1M6B, 2L9U, 3KEX, 3LMG, 3P11, 4LEO, 4OTW, 4P59, 4RIW, 4RIX, 4RIY, 5CUS206513867ENSG00000065361ENSMUSG00000018166P21860Q61526NM_001982NM_001005915NM_010153NP_001005915NP_001973NP_034283Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene.1m6b: Structure of the HER3 (ERBB3) Extracellular Domain Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene. ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. The kinase-impaired ErbB3 is known to form active heterodimers with other members of the ErbB family, most notably the ligand binding-impaired ErbB2. The human ERBB3 gene is located on the long arm of chromosome 12 (12q13). It is encoded by 23,651 base pairs and translates into 1342 amino acids. During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium. ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system. ErbB3, like the other members of the ErbB receptor tyrosine kinase family, consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains four subdomains (I-IV). Subdomains I and III are leucine-rich and are primarily involved in ligand binding. Subdomains II and IV are cysteine-rich and most likely contribute to protein conformation and stability through the formation of disulfide bonds. Subdomain II also contains the dimerization loop required for dimer formation. The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain. Unliganded receptor adopts a conformation that inhibits dimerization. Binding of neuregulin to the ligand binding subdomains (I and III) induces a conformational change in ErbB3 that causes the protrusion of the dimerization loop in subdomain II, activating the protein for dimerization. ErbB3 has been shown to bind the ligands heregulin and NRG-2. Ligand binding causes a change in conformation that allows for dimerization, phosphorylation, and activation of signal transduction. ErbB3 can heterodimerize with any of the other three ErbB family members. The theoretical ErbB3 homodimer would be non-functional because the kinase-impaired protein requires transphosphorylation by its binding partner to be active. Unlike the other ErbB receptor tyrosine kinase family members which are activated through autophosphorylation upon ligand binding, ErbB3 was found to be kinase impaired, having only 1/1000 the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins. Therefore, ErbB3 must act as an allosteric activator. The ErbB2-ErbB3 dimer is considered the most active of the possible ErbB dimers, in part because ErbB2 is the preferred dimerization partner of all the ErbB family members, and ErbB3 is the preferred partner of ErbB2. This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ. There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands.