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. [5]
During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium. [6] ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system. [7]
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. [8] The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain. [9]
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. [9]
ErbB3 has been shown to bind the ligands heregulin [10] and NRG-2. [11] 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. [9]
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. [12] 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. [13] This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ. [14] There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands. [15] [16]
The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K. [17] ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K, [14] a function not found in either EGFR or ErbB2.
While no evidence has been found that ErbB3 overexpression, constitutive activation, or mutation alone is oncogenic, [18] the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis. [19] [20]
ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to:
ErbB2 overexpression may promote the formation of active heterodimers with ErbB3 and other ErbB family members without the need for ligand binding, resulting in weak but constitutive signaling activity. [14]
ERBB3 is expressed in the mesenchyme of the endocardial cushion, which will later develop into the valves of the heart. ErbB3 null mouse embryos show severely underdeveloped atrioventricular valves, leading to death at embryonic day 13.5. Although this function of ErbB3 depends on neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue. [29]
ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system [30] and neural crest derivatives such as Schwann cells. [31]
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
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Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
Neuregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.
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Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.
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The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
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Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.
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Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.
Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene. The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.
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