ERBB3 (HER3) is a member of the EGFR/ERBB family of receptor tyrosine kinases. Unlike other ERBB receptors, it has impaired kinase activity but functions as a signaling hub through heterodimerization, with emerging roles in neural function and neurodegeneration.
ERBB3 (HER3) is a receptor tyrosine kinase of the EGFR family that heterodimerizes with other ERBB receptors to signal. ERBB3 has impaired kinase activity but can activate PI3K/AKT signaling through its partner receptors. In the nervous system, ERBB3 is expressed in neurons and Schwann cells and is important for myelination and neuronal survival. ERBB3 is a target for cancer therapy and has been implicated in neuropathies.
ERBB3 is a receptor tyrosine kinase:
- Extracellular domain: 4 subdomains (I-IV), ligand-binding
- Kinase domain: Inactive due to critical mutations
- C-terminal tail: Multiple tyrosine phosphorylation sites (20+)
Cannot signal as homodimer; requires heterodimerization with ERBB2 or EGFR.
ERBB3 functions through heterodimerization:
- Signal amplification: Partner with ERBB2, EGFR
- PI3K/Akt pathway: Strong activator via Y1301/Y1302 (PI3K docking)
- Neural development: Expressed in developing nervous system
- Schwann cell function: Important for peripheral myelination
- Axonal regeneration: Promotes nerve repair
- Metabolic regulation: Insulin-like effects
Neuregulin-1 (NRG1) is the primary ligand.
- ERBB3 in neural progenitor cells
- May affect neurogenesis
- Implicated in amyloid pathology
- Altered expression in AD
- ERBB3 in dopaminergic neurons
- NRG1-ERBB3 signaling neuroprotective
- May affect α-synuclein toxicity
- Therapeutic potential
- ERBB3 in motor neurons
- Neuregulin signaling impaired
- May affect neuromuscular junction
- Schwann cell function
- Critical for peripheral nerve myelination
- NRG1-ERBB3 in Schwann cells
- Demyelination involves dysregulation
- ERBB3 in post-stroke repair
- Promotes angiogenesis
- May enhance recovery
ERBB3-targeted approaches:
- Anti-ERBB3 antibodies: Patritumab, lumretuzumab
- Ligand-neutralizing antibodies: Anti-NRG1
- ERBB2/ERBB3 bispecific antibodies
- Small molecule inhibitors