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Names & Taxonomy

Uniprot ID:: Q15303
Entry Name:: ERBB4_HUMAN
Status:: reviewed
Protein Names:: Receptor tyrosine-protein kinase erbB-4 (EC 2.7.10.1) (Proto-oncogene-like protein c-ErbB-4) (Tyrosine kinase-type cell surface receptor HER4) (p180erbB4) [Cleaved into: ERBB4 intracellular domain (4ICD) (E4ICD) (s80HER4)]
Gene Names:: ERBB4 HER4
Gene Names Primary:: ERBB4
Organism:: Homo sapiens (Human)

Structure

Length:: 1308
Sequence:: MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVMGNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIFLNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVSTNGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVDSSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCTKINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNLVTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFSTINQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYDGEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGANSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGGLFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQSDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVPYRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQEYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Cell membrane

Function

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 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.
Catalytic Activity:: ATP + a -L-tyrosine = ADP + a -L-tyrosine phosphate.
Enzyme Regulation:: ENZYME REGULATION: Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+). Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.
Active Site:: ACT_SITE 843 843 Proton acceptor.
Cross Reference Drug Bank:: DB08916
Gene Ontology Go:: basolateral plasma membrane
cytosol
extracellular region
integral component of membrane
mitochondrial matrix
mitochondrion
nucleoplasm
nucleus
plasma membrane
receptor complex
ATP binding
epidermal growth factor receptor binding
protein homodimerization activity
protein tyrosine kinase activity
receptor signaling protein tyrosine kinase activity
transcription regulatory region DNA binding
transmembrane receptor protein tyrosine kinase activity
activation of MAPKK activity
axon guidance
cardiac muscle tissue regeneration
cell fate commitment
cell migration
cell proliferation
central nervous system morphogenesis
embryonic pattern specification
epidermal growth factor receptor signaling pathway
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
heart development
innate immune response
insulin receptor signaling pathway
lactation
mammary gland alveolus development
mammary gland epithelial cell differentiation
MAPK cascade
mitochondrial fragmentation involved in apoptotic process
negative regulation of apoptotic process
negative regulation of cell proliferation
negative regulation of neuron migration
nervous system development
neural crest cell migration
neurotrophin TRK receptor signaling pathway
olfactory bulb interneuron differentiation
peptidyl-tyrosine phosphorylation
phosphatidylinositol-mediated signaling
positive regulation of cardiac muscle cell proliferation
positive regulation of cell proliferation
positive regulation of ERK1 and ERK2 cascade
positive regulation of phosphatidylinositol 3-kinase activity
positive regulation of phosphatidylinositol 3-kinase signaling
positive regulation of protein localization to cell surface
positive regulation of protein phosphorylation
positive regulation of STAT protein import into nucleus
positive regulation of transcription, DNA-templated
positive regulation of tyrosine phosphorylation of Stat5 protein
protein autophosphorylation
Ras protein signal transduction
regulation of cell migration
signal transduction
small GTPase mediated signal transduction
transcription, DNA-templated
transmembrane receptor protein tyrosine kinase signaling pathway
vascular endothelial growth factor receptor signaling pathway
Gene Ontology Biological Process:: activation of MAPKK activity
axon guidance
cardiac muscle tissue regeneration
cell fate commitment
cell migration
cell proliferation
central nervous system morphogenesis
embryonic pattern specification
epidermal growth factor receptor signaling pathway
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
heart development
innate immune response
insulin receptor signaling pathway
lactation
mammary gland alveolus development
mammary gland epithelial cell differentiation
MAPK cascade
mitochondrial fragmentation involved in apoptotic process
negative regulation of apoptotic process
negative regulation of cell proliferation
negative regulation of neuron migration
nervous system development
neural crest cell migration
neurotrophin TRK receptor signaling pathway
olfactory bulb interneuron differentiation
peptidyl-tyrosine phosphorylation
phosphatidylinositol-mediated signaling
positive regulation of cardiac muscle cell proliferation
positive regulation of cell proliferation
positive regulation of ERK1 and ERK2 cascade
positive regulation of phosphatidylinositol 3-kinase activity
positive regulation of phosphatidylinositol 3-kinase signaling
positive regulation of protein localization to cell surface
positive regulation of protein phosphorylation
positive regulation of STAT protein import into nucleus
positive regulation of transcription, DNA-templated
positive regulation of tyrosine phosphorylation of Stat5 protein
protein autophosphorylation
Ras protein signal transduction
regulation of cell migration
signal transduction
small GTPase mediated signal transduction
transcription, DNA-templated
transmembrane receptor protein tyrosine kinase signaling pathway
vascular endothelial growth factor receptor signaling pathway
Gene Ontology Molecular Function:: ATP binding
epidermal growth factor receptor binding
protein homodimerization activity
protein tyrosine kinase activity
receptor signaling protein tyrosine kinase activity
transcription regulatory region DNA binding
transmembrane receptor protein tyrosine kinase activity
Gene Ontology Cellular Component:: basolateral plasma membrane
cytosol
extracellular region
integral component of membrane
mitochondrial matrix
mitochondrion
nucleoplasm
nucleus
plasma membrane
receptor complex
Keywords:: 3D-structure
ATP-binding
Activator
Alternative splicing
Amyotrophic lateral sclerosis
Apoptosis
Cell membrane
Complete proteome
Developmental protein
Disease mutation
Disulfide bond
Glycoprotein
Kinase
Lactation
Membrane
Mitochondrion
Neurodegeneration
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Receptor
Reference proteome
Repeat
Signal
Transcription
Transcription regulation
Transferase
Transmembrane
Transmembrane helix
Tyrosine-protein kinase
Ubl conjugation
Interacts With:: P42684; P78352; P00533; P04626; P21860; P08238; P29353; P46937

Names & Taxonomy

Structure

Subcellular location

Function

Publication