ERBB4
ERBB4 (erb-b2 receptor tyrosine kinase 4, also known as HER4 or ALS19) is a cell-surface tyrosine kinase of the EGF receptor subfamily. It binds neuregulins and other EGF family ligands to regulate development of the heart, central nervous system and mammary gland. Browse Assay Genie's current range of ERBB4 research reagents below, or read on for the biology behind the target.
ERBB4 acts as a cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and for the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerisation and autophosphorylation at specific tyrosine residues, which then act as docking sites for scaffold proteins and effectors. ERBB4 mediates phosphorylation of SHC1 and activation of the MAP kinases ERK1 and ERK2. Ligand specificity and signalling are modulated by alternative splicing, proteolytic processing and heterodimer formation with other ERBB family members, producing ligand- and context-specific cellular responses.
Isoform differences shape function. The CYT-1 isoforms phosphorylate PIK3R1, activating phosphatidylinositol 3-kinase and AKT1, protecting cells against apoptosis and promoting actin reorganisation and migration in response to NRG1. The CYT-2 isoforms lack the phosphotyrosine that mediates PIK3R1 interaction and do not have these effects. Proteolytic processing of the JM-A isoforms releases soluble intracellular domains (4ICD) that move to the nucleus, promote STAT5A nuclear import and activation, and drive gene expression. At the CSN2 promoter, 4ICD colocalises with STAT5A to regulate milk protein transcription during lactation. 4ICD can also translocate to mitochondria and promote apoptosis.
The ERBB4 gene encodes a single-pass type I membrane protein with cysteine-rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphatidylinositol 3-kinase binding site and a PDZ domain binding motif. It belongs to the Tyr protein kinase family and the EGF receptor subfamily. ERBB4 is required for cardiac muscle differentiation, postnatal cardiomyocyte proliferation, neural crest cell migration, axon guidance and mammary gland differentiation. Mutations in the gene have been associated with cancer. Earlier names include v-erb-a avian erythroblastic leukaemia viral oncogene homolog-like 4.
ERBB4 is required for normal cardiac muscle differentiation in the embryo and for postnatal cardiomyocyte proliferation.
The receptor is needed for normal development of the embryonic central nervous system, including neural crest cell migration and axon guidance.
ERBB4 supports mammary epithelium differentiation, induction of milk proteins and lactation, partly via nuclear 4ICD and STAT5A.
Mutations in ERBB4 have been associated with cancer, and its isoform-specific PI3K, AKT and MAPK signalling affects proliferation, migration and apoptosis.
ERBB4 is a receptor tyrosine kinase for neuregulins and EGF family ligands. Ligand binding causes dimerisation and autophosphorylation, activating effectors such as SHC1, MAP kinases and PI3K/AKT. It regulates heart, central nervous system and mammary gland development, as well as proliferation, differentiation, migration and apoptosis.
ERBB4 is also called HER4 and ALS19, and was previously named v-erb-a avian erythroblastic leukaemia viral oncogene homolog-like 4. Alternative splicing yields JM-A and JM-B juxtamembrane forms, each with CYT-1 or CYT-2 cytoplasmic tails, which differ in PIK3R1 phosphorylation, anti-apoptotic activity and cell migration.
Orthologs of ERBB4 are annotated in mouse and rat, where the gene is called Erbb4. The NCBI Gene summary reports that mutations in human ERBB4 have been associated with cancer. Check the datasheet of any product for its validated reactivity.
Other ERBB family receptors, neuregulin and EGF family ligands, and downstream signalling proteins linked to ERBB4.
Gene and protein annotations from HGNC, NCBI Gene and UniProt Q15303; product specifications from Assay Genie datasheets.