ERBB4 - Receptor tyrosine-protein kinase erbB-4 - human protein (Function)
 
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ERBB4 »  Receptor tyrosine-protein kinase erbB-4   [ EC 2.7.10.1 ]
 
Protein also known as:  Tyrosine kinase-type cell surface receptor HER4. Cleaved into:  ERBB4 intracellular domain.
Gene name:  ERBB4
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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.  
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  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Epidermal growth factor receptor bindingdefinition[GO:0005154]  
1
  • IPIUniProtKB
Protein bindingdefinition[GO:0005515]  
10
  • IPIIntAct
  • IPIUniProtKB
Protein homodimerization activitydefinition[GO:0042803]  
1
  • IPIUniProtKB
Protein tyrosine kinase activitydefinition[GO:0004713]  
1
  • IDAUniProtKB
Receptor signaling protein tyrosine kinase activitydefinition[GO:0004716] silver  
  • IEAInterPro 2 GO
Transcription regulatory region DNA bindingdefinition[GO:0044212]  
1
  • IMPUniProtKB
Transmembrane receptor protein tyrosine kinase activitydefinition[GO:0004714]  
1
  • IDAUniProtKB
GO biological process 
Cardiac muscle tissue regenerationdefinition[GO:0061026]  
  • ISSOrtholog Curator
Cell fate commitmentdefinition[GO:0045165] silver  
  • IEAOrtholog Compara
Cell migrationdefinition[GO:0016477]  
1
  • IDAUniProtKB
Cell proliferationdefinition[GO:0008283]  
1
  • TASPINC
Central nervous system morphogenesisdefinition[GO:0021551]  
  • ISSOrtholog Curator
Embryonic pattern specificationdefinition[GO:0009880]  
  • ISSOrtholog Curator
Heart developmentdefinition[GO:0007507]  
  • ISSOrtholog Curator
Lactationdefinition[GO:0007595]  
1
  • IMPUniProtKB
Mammary gland alveolus developmentdefinition[GO:0060749]  
  • ISSOrtholog Curator
Mammary gland epithelial cell differentiationdefinition[GO:0060644]  
  • ISSOrtholog Curator
Mitochondrial fragmentation involved in apoptotic processdefinition[GO:0043653]  
1
  • IMPUniProtKB
Isoform  JM-A CYT-1   Negative regulation of apoptotic processdefinition[GO:0043066]  
1
  • IMPUniProtKB
Negative regulation of cell proliferationdefinition[GO:0008285]  
1
  • IMPUniProtKB
Nervous system developmentdefinition[GO:0007399]  
  • ISSOrtholog Curator
Neural crest cell migrationdefinition[GO:0001755]  
  • ISSOrtholog Curator
Olfactory bulb interneuron differentiationdefinition[GO:0021889]  
  • ISSOrtholog Curator
Peptidyl-tyrosine phosphorylationdefinition[GO:0018108]  
1
  • IDAUniProtKB
Positive regulation of cardiac muscle cell proliferationdefinition[GO:0060045]  
  • ISSOrtholog Curator
Positive regulation of cell proliferationdefinition[GO:0008284]  
2
  • IMPUniProtKB
Positive regulation of ERK1 and ERK2 cascadedefinition[GO:0070374]  
1
  • IMPUniProtKB
Isoforms  JM-A CYT-1 and JM-B CYT-1 but not isoforms  JM-A CYT-2 and JM-B CYT-2   Positive regulation of phosphatidylinositol 3-kinase activitydefinition[GO:0043552]  
1
  • IDAUniProtKB
Positive regulation of protein phosphorylationdefinition[GO:0001934]  
1
  • TASUniProtKB
Positive regulation of STAT protein import into nucleusdefinition[GO:2000366]  
1
  • IMPUniProtKB
Positive regulation of transcription, DNA-templateddefinition[GO:0045893]  
1
  • IMPUniProtKB
Positive regulation of tyrosine phosphorylation of Stat5 proteindefinition[GO:0042523]  
1
  • IMPUniProtKB
Protein autophosphorylationdefinition[GO:0046777]  
1
  • IDAUniProtKB
Regulation of cell migrationdefinition[GO:0030334]  
  • ISSOrtholog Curator
Signal transductiondefinition[GO:0007165]  
1
  • IDAUniProtKB
Signal transduction by phosphorylationdefinition[GO:0023014]  
  • IEAInterPro 2 GO
Transcription, DNA-templateddefinition[GO:0006351]  
  • IEAUniProtKB KW
Transmembrane receptor protein tyrosine kinase signaling pathwaydefinition[GO:0007169]  
2
  • IDAUniProtKB
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.10.1: ATP + a [protein]-L-tyrosine ADP + a [protein]-L-tyrosine phosphate.  
4
  • CuratedUniProtKB
It is regulated in the following manner
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.  
5
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Calcium signaling pathway  hsa04020+2066  
Endocytosis  hsa04144+2066  
ErbB signaling pathway  hsa04012+2066  
According to Reactome, this protein belongs to the following pathways:
Constitutive PI3K/AKT Signaling in Cancer  REACT_147727  
Downregulation of ERBB4 signaling  REACT_115828  
GRB2 events in ERBB2 signaling  REACT_115854  
Nuclear signaling by ERBB4  REACT_116022  
PI3K events in ERBB2 signaling  REACT_116008  
PI3K events in ERBB4 signaling  REACT_115961  
PIP3 activates AKT signaling  REACT_75829  
SHC1 events in ERBB2 signaling  REACT_115993  
SHC1 events in ERBB4 signaling  REACT_116005  
Signaling by ERBB2  REACT_115755  
Signaling by ERBB4  REACT_115596  
Caution 
Conflicting reports about the role of ERBB4 in mediating apoptosis, differentiation, or tumor cell proliferation may be explained by the opposite functions of the different isoforms and their intracellular fragments, and by the formation of heterodimers with other EGF receptor family members (PubMed18454307 and PubMed21811097). Thus, heterodimer formation of a kinase-dead ERBB4 mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2 and MAPK3/ERK1 (PubMed19098003).  
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  • CuratedUniProtKB
 

Keywords

Biological process 
Apoptosis  definition   [KW-0053]
Lactation  definition   [KW-0421]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Activator  definition   [KW-0010]
Developmental protein  definition   [KW-0217]
Kinase  definition   [KW-0418]
Receptor  definition   [KW-0675]
Transferase  definition   [KW-0808]
Tyrosine-protein kinase  definition   [KW-0829]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: ERBB4
GenomeRNAi: 2066
PRO: PR:Q15303
Chemistry
GuidetoPHARMACOLOGY: 1799