| Function: |
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 s 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. |
| Tissue Specificity: |
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. |
| Involvement in Disease: |
Amyotrophic lateral sclerosis 19: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. |
| Sequence Similarities: |
Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. |
| Post-Translational Modification: |
Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalsence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase. |
| Cellular locations: |
Cell membrane.
In response to NRG1 treatment, the activated receptor is internalized. |
| Database Links: |
Entrez Gene: 2066 HumanEntrez Gene: 13869 MouseEntrez Gene: 59323 RatOmim: 600543 HumanSwissProt: Q15303 HumanSwissProt: Q61527 MouseSwissProt: Q62956 RatUnigene: 390729 HumanUnigene: 442420 MouseUnigene: 163078 Rat |
| Synonyms: |
4ICD AntibodyALS19 AntibodyAvian erythroblastic leukemia viral oncogene homolog 4 AntibodyAvian erythroblastic leukemia viral v erb b2 oncogene homolog 4 AntibodyE4ICD AntibodyEC 2.7.10.1 AntibodyErbB 4 AntibodyErbb4 AntibodyERBB4 intracellular domain AntibodyERBB4_HUMAN AntibodyHER 4 AntibodyHER4 Antibodyhuman epidermal growth factor receptor 4 AntibodyMer4 AntibodyMGC138404 AntibodyOncogene ERBB4 Antibodyp180erbB4 AntibodyProto-oncogene-like protein c-ErbB-4 AntibodyReceptor protein tyrosine kinase erbB 4 precursor AntibodyReceptor tyrosine protein kinase erbB 4 Antibodys80HER4 AntibodyTyrosine kinase type cell surface receptor HER4 AntibodyTyrosine kinase-type cell surface receptor HER4 Antibodyv erb a avian erythroblastic leukemia viral oncogene homolog like 4 Antibodyv erb a erythroblastic leukemia viral oncogene homolog 4 Antibodyv-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) AntibodyV-ERB-B2 avian erythroblastic leukemia viral oncogene homolog 4 AntibodyVerba avian erythroblastic leukemia viral oncogene homolog like 4 AntibodyVerba erythroblastic leukemia viral oncogene homolog 4 AntibodyVERBB2 Antibody |
| Information: |
Target information shown above is from the UniProt Consortium. |
