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.
Chromosome 12
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.
ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, intestinal epithelium, 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).
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 is kinase impaired, having only 1/1000 the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins.
It must act as an allosteric activator.
The ErbB2-ErbB3 dimer is considered the most active of the possible ErbB dimers.
ErbB3 is the preferred partner of ErbB2.
This heterodimer conformation allows the signaling complex to activate multiple pathways: MAPK, PI3K/Akt, and PLCγ.
ErbB3 overexpression, activation, or mutation alone is not oncogenic.
The ErB3 protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis.
ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to:
HER2 inhibitors in HER2+ breast cancers
anti-estrogen therapy in ER+ breast cancers
EGFR inhibitors in lung and head and neck cancers
hormones in prostate cancers
IGF1R inhibitors in hepatomas
BRAF inhibitors in melanoma
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.
ERBB3 expression in the mesenchyme of the endocardial cushion, that develops into the valves of the heart.
ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system and neural crest derivatives such as Schwann cells.