ErbB4

ErbB4, also known as HER4, is a receptor tyrosine kinase member of the epidermal growth factor receptor (EGFR/ErbB) family. It binds ligands from the neuregulin family, particularly neuregulin-1, and forms signaling heterodimers with other ErbB receptors, most commonly with ErbB2 (HER2). Activation leads to autophosphorylation on tyrosine residues and recruitment of SH2-domain signaling proteins, triggering downstream pathways such as PI3K–Akt and MAPK/ERK that regulate cell differentiation, proliferation, and survival.

The ErbB4 protein consists of an extracellular ligand-binding domain with four subdomains, a single transmembrane helix, and an intracellular tyrosine kinase domain followed by a cytoplasmic tail. Alternative splicing in the juxtamembrane region yields isoforms with differing susceptibility to proteolytic processing, notably JM-a and JM-b. JM-a can be cleaved by metalloproteases (e.g., ADAM family), producing a membrane-tunted fragment that is further processed by gamma-secretase to release the intracellular domain (4ICD). The 4ICD can translocate to the nucleus or mitochondria, where it can influence gene expression and apoptotic pathways.

In development, ErbB4 signaling is important for cardiac development, including trabeculation and myocyte proliferation, and for nervous system processes such as synapse formation and interneuron migration. In humans, alterations in ErbB4 expression or signaling have been observed in several cancers, where its role appears context-dependent and may range from tumor suppressor to oncogenic effects. At the cellular level, ErbB4 interacts with ErbB2 and with scaffold proteins such as PSD-95 in neurons, integrating signals that shape cellular responses.