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ERBB3
erb-b2 receptor tyrosine kinase 3
The ERBB3 gene provides instructions for making a protein involved in growth factor signalling, influencing cell proliferation, differentiation, and survival. The ERBB3 gene produces the erb-b2 receptor tyrosine kinase 3 protein, a member of the epidermal growth factor receptor (EGFR) family.
ERBB3 is located on the long (q) arm of chromosome 12, at band 12q13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The ERBB3 gene, also known as HER3, is part of the ERBB family of receptor tyrosine kinases. These proteins are cell surface receptors that bind to growth factors, initiating intracellular signalling cascades. ERBB3 is distinctive within this family as it has impaired kinase activity but is essential for signalling through heterodimerisation with other ERBB family members, especially ERBB2.
Dysregulation of ERBB3 signalling has been implicated in various diseases, including certain cancers and autoimmune conditions. Understanding its function is important for deciphering complex biological processes and potential therapeutic targets.
What the gene does
The ERBB3 protein functions as a receptor for growth factors, primarily heregulins (also known as neuregulins). Upon binding these ligands, ERBB3 forms heterodimers with other ERBB family members, most notably ERBB2. This dimerisation facilitates the activation of downstream signalling pathways, such as the PI3K/Akt and MAPK pathways, which are critical for regulating cell proliferation, survival, migration, and differentiation.
Unlike other ERBB receptors, ERBB3 exhibits weak or absent intrinsic tyrosine kinase activity. Instead, its signalling capacity largely depends on its ability to act as an allosteric activator, presenting numerous phosphorylation sites for other ERBB partners, thereby recruiting adaptor proteins that initiate downstream cascades. This unique characteristic makes ERBB3 a crucial component in ERBB signalling networks, despite its catalytic deficiency.
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Chromosome location
The ERBB3 gene is located on the long arm of chromosome 12 at position 13.2, which is denoted as 12q13.2. This specific genomic location positions ERBB3 within a region known to house several genes important for cellular regulation and development.
Protein structure
The ERBB3 protein spans 1342 amino acids and includes a key functional region crucial for its activity. It contains a Protein kinase domain located between amino acids 709 and 966. Additionally, there are two important Disordered regions: one spanning amino acids 980-999 and another larger region from amino acids 1033-1152. These domains and regions contribute to its role in cell signalling and interaction with other proteins.
Key variants
Genetic variations within the ERBB3 gene can influence how the protein functions or is expressed. These variations may include single nucleotide changes, insertions, or deletions. While some variants might have no discernible effect, others could alter protein activity, potentially influencing disease susceptibility or progression.
Sample of pathogenic variants
7 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1914-7C>G | - | Pathogenic | ★☆☆☆ | Visceral neuropathy, familial, 1, autosomal recessive |
c.2942_2945del | - | Pathogenic | ★☆☆☆ | Visceral neuropathy, familial, 1, autosomal recessive |
c.180G>A | p.Met60Ile | Pathogenic | - | Malignant tumor of urinary bladder |
c.2782G>A | p.Glu928Lys | Pathogenic | - | Malignant tumor of urinary bladder |
c.307C>T | p.Arg103Cys | Pathogenic | - | Malignant tumor of urinary bladder |
c.310G>A | p.Val104Met | Pathogenic | - | Malignant tumor of urinary bladder |
c.3297del | p.His1100fs | Pathogenic | - | Visceral neuropathy, familial, 1, autosomal recessive |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the ERBB3 gene have been implicated in a range of conditions, particularly within the context of polygenic inheritance, where multiple genes and environmental factors contribute to risk. Research suggests associations with autoimmune disorders, though the exact mechanisms are still under investigation. The inheritance pattern for conditions related to ERBB3 is considered polygenic, indicating a complex genetic contribution.
No disease links recorded for this gene in our reference set.
UK clinical status
The ERBB3 gene is included in several NHS Genomic Medicine Service national panels. It is reviewed in the Arthrogryposis panel (R83), the DDG2P panel, the Foetal anomalies panel (R21), and the Paediatric pseudo-obstruction syndrome panel (R438). Its presence on these panels indicates its clinical relevance for diagnostics within the UK health system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ERBB3 gene do?
The ERBB3 gene provides instructions for making the erb-b2 receptor tyrosine kinase 3 protein, which is involved in cell signalling pathways. This protein helps regulate cell growth, division, and survival by receiving signals from outside the cell.
Is ERBB3 associated with any conditions?
Yes, variations in the ERBB3 gene have been associated with polygenic conditions, including certain autoimmune disorders. Its role in complex cell signalling pathways means that alterations can contribute to disease susceptibility.
What is unique about the ERBB3 protein compared to other ERBB family members?
Unlike other members of the ERBB receptor family, the ERBB3 protein has significantly reduced intrinsic tyrosine kinase activity. It primarily functions by forming heterodimers with other ERBB proteins, particularly ERBB2, to facilitate downstream signalling.