InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ERBB4

Summary

InnateDB Protein

IDBP-293096.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ERBB4

Protein Name

v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)

Synonyms

ALS19; HER4; p180erbB4;

Species

Homo sapiens

Ensembl Protein

ENSP00000385565

InnateDB Gene

IDBG-79992 (ERBB4)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:10348342, ECO:0000269PubMed:10353604, ECO:0000269PubMed:10358079, ECO:0000269PubMed:10722704, ECO:0000269PubMed:10867024, ECO:0000269PubMed:11178955, ECO:0000269PubMed:11390655, ECO:0000269PubMed:12807903, ECO:0000269PubMed:15534001, ECO:0000269PubMed:15746097, ECO:0000269PubMed:16251361, ECO:0000269PubMed:16778220, ECO:0000269PubMed:16837552, ECO:0000269PubMed:17486069, ECO:0000269PubMed:17638867, ECO:0000269PubMed:19098003, ECO:0000269PubMed:20858735, ECO:0000269PubMed:8383326, ECO:0000269PubMed:8617750, ECO:0000269PubMed:9135143, ECO:0000269PubMed:9168115, ECO:0000269PubMed:9334263}.

Subcellular Localization

Cell membrane {ECO:0000269PubMed:10348342, ECO:0000269PubMed:12807903, ECO:0000269PubMed:15534001, ECO:0000269PubMed:16251361, ECO:0000269PubMed:16778220, ECO:0000269PubMed:16837552, ECO:0000269PubMed:17486069, ECO:0000269PubMed:17638867, ECO:0000269PubMed:19193720, ECO:0000269PubMed:20858735, ECO:0000269PubMed:8383326, ECO:0000269PubMed:9334263}; Single-pass type I membrane protein {ECO:0000269PubMed:10348342, ECO:0000269PubMed:12807903, ECO:0000269PubMed:15534001, ECO:0000269PubMed:16251361, ECO:0000269PubMed:16778220, ECO:0000269PubMed:16837552, ECO:0000269PubMed:17486069, ECO:0000269PubMed:17638867, ECO:0000269PubMed:19193720, ECO:0000269PubMed:20858735, ECO:0000269PubMed:8383326, ECO:0000269PubMed:9334263}. Note=In response to NRG1 treatment, the activated receptor is internalized.ERBB4 intracellular domain: Nucleus {ECO:0000269PubMed:17486069}. Mitochondrion {ECO:0000269PubMed:17486069}. Note=Following proteolytical processing E4ICD (E4ICD1 or E4ICD2 generated from the respective isoforms) is translocated to the nucleus. Significantly more E4ICD2 than E4ICD1 is found in the nucleus. E4ICD2 colocalizes with YAP1 in the nucleus.

Disease Associations

Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: 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. {ECO:0000269PubMed:24119685}. Note=The disease is caused by mutations affecting the gene represented in this entry.

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. {ECO:0000269PubMed:10353604, ECO:0000269PubMed:8383326, ECO:0000269PubMed:9334263}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 82 experimentally validated interaction(s) in this database.
They are also associated with 1 interaction(s) predicted by orthology.

Experimentally validated
Total	82 [view]
Protein-Protein	81 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	1 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0004716	receptor signaling protein tyrosine kinase activity
GO:0005154	epidermal growth factor receptor binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042803	protein homodimerization activity
GO:0044212	transcription regulatory region DNA binding

Biological Process

GO:0001755	neural crest cell migration
GO:0001934	positive regulation of protein phosphorylation
GO:0006351	transcription, DNA-templated
GO:0006468	protein phosphorylation
GO:0007165	signal transduction
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007399	nervous system development
GO:0007507	heart development
GO:0007595	lactation
GO:0008283	cell proliferation
GO:0008284	positive regulation of cell proliferation
GO:0008285	negative regulation of cell proliferation
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0009880	embryonic pattern specification
GO:0016477	cell migration
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0021551	central nervous system morphogenesis
GO:0021889	olfactory bulb interneuron differentiation
GO:0023014	signal transduction by phosphorylation
GO:0030334	regulation of cell migration
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0042523	positive regulation of tyrosine phosphorylation of Stat5 protein
GO:0043066	negative regulation of apoptotic process
GO:0043552	positive regulation of phosphatidylinositol 3-kinase activity
GO:0043653	mitochondrial fragmentation involved in apoptotic process
GO:0045087	innate immune response
GO:0045893	positive regulation of transcription, DNA-templated
GO:0046777	protein autophosphorylation
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0060045	positive regulation of cardiac muscle cell proliferation
GO:0060644	mammary gland epithelial cell differentiation
GO:0060749	mammary gland alveolus development
GO:0061026	cardiac muscle tissue regeneration
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:2000366	positive regulation of STAT protein import into nucleus

Cellular Component

GO:0005576	extracellular region
GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005739	mitochondrion
GO:0005759	mitochondrial matrix
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0016020	membrane
GO:0016021	integral component of membrane
GO:0016323	basolateral plasma membrane
GO:0043235	receptor complex

Protein Structure and Domains

PDB ID

InterPro

IPR000494 EGF receptor, L domain
IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR006211 Furin-like cysteine-rich domain
IPR006212 Furin-like repeat
IPR009030 Insulin-like growth factor binding protein, N-terminal
IPR011009 Protein kinase-like domain
IPR016245 Tyrosine protein kinase, EGF/ERB/XmrK receptor
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF01030
PF00069
PF07714
PF00757

PRINTS

PR00109

PIRSF

PIRSF000619

SMART

SM00220
SM00261
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References