Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart. 4 alternatively spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Protein type: EC 184.108.40.206; EGFR family; Kinase, protein; Membrane protein, integral; Protein kinase, TK; Protein kinase, tyrosine (receptor); TK group
Cellular Component: basal plasma membrane; basolateral plasma membrane; caveola; cytoplasm; GABA-ergic synapse; glutamatergic synapse; integral component of membrane; integral component of plasma membrane; integral component of postsynaptic density membrane; integral component of presynaptic membrane; membrane; membrane raft; mitochondrion; nucleus; plasma membrane; postsynaptic density; postsynaptic membrane; receptor complex
Molecular Function: ATP binding; epidermal growth factor receptor binding; kinase activity; neuregulin binding; nucleotide binding; protein binding; protein homodimerization activity; protein kinase activity; protein tyrosine kinase activity; transcription regulatory region DNA binding; transferase activity; transmembrane receptor protein tyrosine kinase activity
Biological Process: apoptotic process; cardiac muscle tissue regeneration; cell fate commitment; cell migration; cellular response to epidermal growth factor stimulus; central nervous system morphogenesis; embryonic pattern specification; heart development; lactation; mammary gland alveolus development; mammary gland epithelial cell differentiation; mitochondrial fragmentation involved in apoptotic process; multicellular organism development; negative regulation of apoptotic process; negative regulation of cell proliferation; negative regulation of muscle cell apoptotic process; negative regulation of neuron migration; nervous system development; neural crest cell migration; olfactory bulb interneuron differentiation; peptidyl-tyrosine autophosphorylation; peptidyl-tyrosine phosphorylation; phosphorylation; positive regulation of apoptotic process; positive regulation of cardiac muscle cell proliferation; positive regulation of cell migration; positive regulation of cell proliferation; positive regulation of epithelial cell proliferation; positive regulation of ERK1 and ERK2 cascade; positive regulation of glucose import; positive regulation of JAK-STAT cascade; positive regulation of phosphatidylinositol 3-kinase signaling; positive regulation of protein localization to cell surface; positive regulation of synaptic transmission, GABAergic; positive regulation of transcription, DNA-templated; positive regulation of tyrosine phosphorylation of STAT protein; protein autophosphorylation; protein phosphorylation; regulation of cell migration; signal transduction; surfactant homeostasis; synapse assembly; synapse maturation; transmembrane receptor protein tyrosine kinase signaling pathway