ERBB3

Fig1. Schematic representation of the structural changes and activation of ErbB/HER receptors.

What is ERBB3 protein?

ERBB3 (erb-b2 receptor tyrosine kinase 3) is a protein coding gene which situated on the long arm of chromosome 12 at locus 12q13. ERBB3, also known as Her3 (human epidermal growth factor receptor 3), is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound glycoprotein has a neuregulin binding domain but no active kinase domain. It therefore can bind the ligand but cannot mediate the intracellular signal transduction through protein phosphorylation. This protein has different isoforms derived from alternative splicing variants, and among which, the secreted isoform lacking the intermembrane region modulates the activity of membrane-bound form. The ERBB3 protein is consisted of 1342 amino acids and its molecular mass is approximately 148 kDa.

What is the function of ERBB3 protein?

The main function of ERBB3 is to promote cell growth, survival, and differentiation through the activation of various intracellular signaling cascades. Upon binding of ligands such as heregulins (HRG), neuregulins (NRG), and other EGF family members, ERBB3 forms heterodimers with ERBB2 or other EGFR family members. This interaction leads to the activation of several downstream signaling pathways, including the PI3K-AKT and MAPK-ERK pathways. And it is involved in the regulation of myeloid cell differentiation.

ERBB3 related Signaling pathways

Some of the major signaling pathways associated with ERBB3 include: PI3K-AKT pathway, MAPK pathway. ERBB3 can activate the Janus kinases (JAKs) and subsequent signaling through the signal transducer and activator of transcription (STAT) proteins. ERBB3 can also form heterodimers with other ErbB family members such as ERBB1 (EGFR), ERBB2 (HER2), and ERBB4 (HER4) to activate more downstream signaling pathways.

ERBB3 Related Diseases

Overexpression of this protein has been reported in numerous cancers, including prostate, bladder, and breast tumors. Additionally, ERBB3 has been implicated in the regulation of neuronal and cardiac development. What's more, Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3)that affect the function of the phosphatidylinositol-3-kinase /Akt pathway. A germline ERBB3 variant is also a candidate for predisposition to erythroid MDS/erythroleukemia. Another report found that dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.

Bioapplications of ERBB3

Drug development targeting ERBB3 has become an important therapeutic strategy. For example, Trastuzumab (Herceptin), a monoclonal antibody drug that targets ERBB3, has been widely used in the treatment of HER2-positive breast cancer. In addition, the expression level of ERBB3 can be used as an important indicator for tumor diagnosis and prognosis evaluation. Manipulating ERBB3 signaling pathways can enhance or inhibit stem cell differentiation, which has applications in regenerative medicine and disease modeling.