The ERBB3 gene, which maps to human chromosome 12q13.2, is 23.2 kb in size and consists of 28 exons. The gene for the extracellular ligand binding domain of ErbB3 has 43-45% homology with EGFR and ERBB2 and 56-67% homology with ERBB4. The cytoplasmic tyrosine kinase domain sequences have 60-63% homology with those of the other ErbB receptors (Kraus et al., 1989).

The ERBB3 promoter region is GC rich (65%) and, like EGFR, does not contain a TATA box. A proximal promoter was observed within 600 bp flanking Exon1. AP2-1 (OB2-1) and Fox3a have been demonstrated to be functional transcriptional regulators at upstream start sites (Skinner and Hurst, 1993). A Sox10 regulated enhancer has been identified at chr12:54763065-54763421 in neural crest derived cells. The human ERBB3 gene is transcribed as a 6.2 kb message of 4080 nucleotides and 1342 codons specifying the full-length protein. There are four additional alternate transcripts of 1.6, 1.7, 2.1 and 2.3 kb generated by intron read through. At least three of these transcripts code for truncated, secreted soluble forms of ERBB3 (Lee and Maihle, 1998).

None reported.

The ERBB3 gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. The 6.2 kb transcript encodes a 148 kDa protein which is post-translationally glycosylated to yield a protein of 180 kDa (Kraus et al., 1989). The extracellular ligand-binding domain consists of four subdomains that change conformation in response to ligand. Domains I and III bind NRG with high affinity (Cho and Leahy, 2002). Due to substitutions in the kinase domain at aa 740, 759 and 834, ErbB3 lacks potent tyrosine kinase activity. However, recent data indicate that ErbB3 maintains some autophosphorylation activity (Shi et al., 2010). Heterodimerization with other ErbB family members, most notably ErbB2, is needed to convey biological signals through phosphorylation of downstream substrates, most notably AKT (Olayioye et al., 2000). In general, activation of these pathways leads to cell proliferation or differentiation. Alternate transcriptional splice variants encoding different isoforms have been characterized. Each alternate transcript encodes a truncated form of the ligand-binding domain of ErbB3 and can compete for binding with ligand, resulting in growth inhibition (Lee et al., 2001).
ErbB3 is post translationally regulated by a variety of mechanisms. After ligand binding, it is phosphorylated on 14 tyrosine residues by other ErbB family members (Kim et al., 1998) and under some circumstance c-Src, Met and BRK. Protein levels are regulated by the E3 ligase Nrdp1 and the Nrdp1 regulator USP8. USP8 itself is regulated by AKT, suggesting a feedback mechanism for ErbB activity (Wu et al., 2004).

ErbB3 is widely expressed in embryonic and adult tissues. It is expressed in epithelial cells of the gastrointestinal, respiratory, reproductive and urinary tracts as well as the skin and endocrine systems. It is highly expressed in neuronal tissue. Expression is relatively low in cells of the hematopoietic and immune systems (Kraus et al., 1989; Prigent et al., 1992).

ErbB3 is generally located in the plasma membrane. However, more recent studies indicate that ErbB3 is also localized to the nucleus (Offterdinger et al., 2002).

Activation and interactions
ErbB3 when localized at the plasma membrane binds different forms of neuregulin. The NRG family consists of a large group of isoforms, encoded by four genes with an EGF like C terminal portion and a variable N terminal region. Ligand binding leads to heterodimerization preferentially with ErbB2, but also other ErbB family members in secondary reactions (Pinkas-Kramarski et al., 1996). The transmembrane domain, which binds EBP1, is important for dimer stabilization (Jura et al., 2009). The cytoplasmic domain lacks potent tyrosine kinase activity. However, this domain has been shown to be an allosteric activator of the ErbB2 kinase domain (Zhang et al., 2006). The cytoplasmic tail of ErbB3 is phosphorylated by ErbB2 and is a signaling substrate. The 14 phosphorylated tyrosines in the C terminal signaling tail of ErbB3 can potentially dock numerous SH2/3 or PTB binding proteins involved in different biological pathways (Hynes and Lane, 2005).

Signaling and cellular activity
In contrast to other ErbB proteins, ErbB3 is not transforming when overexpressed or constitutively activated (Alimandi et al., 1995). Once phosphorylated by other ErbB family members or Src, Met or BRK, ErbB-3 can then bind numerous other signaling proteins. Activation of the PI-3 kinase-AKT pathway is especially important as there are six docking sites for the p85 subunit of PI-3K in the ErbB3 cytoplasmic tail at Tyr 1035, 1178, 1203/1205, 1257 and 1270. AKT regulates many downstream signaling nodes, in particular the two mTOR containing complexes. ErbB3 can also activate the MAPK pathway via its interactions with Grb7 (Tyr 1180,1243) and SHC (1309) (Hynes and Lane, 2005). Thus, ErbB3 is important in biological processes such as translation, apoptosis, nutrient sensing, metabolic regulation, angiogenesis and cell cycle control. Increased expression or activity of ErbB3 has been associated with resistance to EGFR and ErbB2 inhibitors (Sergina et al., 2007) and hormonal therapies (Liu et al., 2007). ErbB3 when localized in the nucleus acts as a transcription factor to regulate Cyclin D1 and β-casein genes (Andrique et al., 2012).

Physiological
ErbB3 knock-out mice die by E13.5 with defective heart valve formation, but normal heart trabeculation. The animals show a generalized neural crest defects and lack Schwann cell precursors (Erickson et al., 1997). Due to the importance of ErbB3 in breast cancer, the role of ErbB3 in mammary development has been well-studied. ErbB3 is required for ductal morphogenesis in the mouse mammary gland (Stern, 2003). ErbB3 has also been implicated in maintenance of the luminal epithelial subtype in the breast (Balko et al., 2012).

The ErbB family has evolved from a single ligand-receptor combination in C. elegans (let-23 28% aa similarity) through Drosophila with one receptor (EGFR, 39% similarity) and four ligands to vertebrates, where four ErbB receptor bind multiple EGF-related ligands. The ERBB3 gene is conserved in chimpanzee (99% similarity), dog, cow, mouse (90%), rat, chicken, and zebrafish.

An A to G mutation is noted in intron 10 in Lethal Congential Contracture Syndrome 2 (LCCS2). LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord (Narkis et al., 2004).

Mutations in ErbB3 have been rarely noted in cancer. One of the 2 mutations reported was a missense mutation in exon 21 (2537 G > T) (Ser846Ile) detected in a rectal mucinous adenocarcinoma (1% of the total colon cancer samples. The other mutation was a silent mutation in exon 21 (2484 T > C) (His828His) detected in an invasive ductal carcinoma of the breast (2% of the total 60 breast cancers) (Jeong et al., 2006).