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FLASH GENE

Symbol

ERBB4

contributors: mct - updated : 03-10-2015

HGNC name	v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)
HGNC id	3432

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ALS19 amyotrophic lateral sclerosis 19
Location	2q34      Physical location : 212.240.441 - 213.403.352
Synonym name	avian erythroblastic leukemia viral (v-erb-b2) oncogene homolog 4
	receptor tyrosine-protein kinase erbB-4
	tyrosine kinase-type cell surface receptor HER4
Synonym symbol(s)	HER4, MGC138404, p180erbB4
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	1162.91 kb     28 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	alternatively spliced producing juxtamembrane (JM-a and JM-b) and cytoplasmic (CYT-1 and CYT-2) isoforms (PMID; 20943952)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005235 28 splicing 11941 NP_005226 146.8 1308 - 2010 20886074 efficiently endocytosed precursor having PPXY motif within the CYT-1-specific sequence that lacks from CYT-2, necessary both for ubiquitination and endocytosis of CYT-1 isoforms and provided a binding site for a WW domain-containing ubiquitin ligase ITCH JM-a/CYT-1 fibroblasts expressing ERBB4 JM-a demonstrated enhanced ERBB4 autophosphorylation, growth, and survival variant Jmb - splicing 40 isoform Jmb - 15 heart, cerebellum 2010 20943952 cells overexpressing ERBB4 JM-b underwent starvation-induced death variant Jmc - splicing - isoform Jmv - - cerebellum 2001 11391800 variant Jmd - splicing - isoform Jmd - - developing fetal cerebellum only 2001 11391800 NM_001042599 27 splicing 11893 NP_001036064 - 1292 - 2010 20886074 precursor also called JM-a, CYT-2 novel splice isoforms of ErbB4, whereby exon 3 is skipped (del.3). ERBB4 del.3 transcripts exist as CYT-2 isoforms and are predicted to produce truncated proteins

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Endocrine neuroendocrine       moderately   parathyroid       highly Lymphoid/Immune spleen       moderately Nervous brain hindbrain cerebellum   moderately Reproductive female system breast mammary gland   highly   male system testis     moderately Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum cardiac     Homo sapiens Muscular striatum skeletal   highly

cells

System Cell Pubmed Species Stage Rna symbol Muscular myocyte Homo sapiens

cell lineage
cell lines	breast carcinoma cell line
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a single transmembrane protein with extensive homology to the epidermal growth factor receptor
	extracellular juxtamembrane domain (JM-a and JM-b forms)
	intracellular cytoplasmic domain (CYT-1 and CYT-2)
	specific N-glycan in domain III playing an essential role in regulating receptor dimerization and transforming activity
	a cytoplasmic catalytic domain with a sequence in the C terminal terminal binding the PDZ domain of MAGUKs protein
	a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645-657)) in the juxtamembrane region

conjugated

GlycoP

mono polymer

homomer , heteromer , dimer , trimer

HOMOLOGY

interspecies	ortholog to murine Erbb4
	ortholog to rattus Erbb4

intraspecies

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

Homologene

FAMILY	epidermal growth factor family
	type I receptor tyrosine kinase subfamily

CATEGORY

enzyme , protooncogene , receptor membrane tyrosine kinase

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria,matrix
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
text	integral to plasma membrane; type I membrane protein
	localizes to the nucleus as a full-length protein (PMID;

basic FUNCTION	receptor tyrosine kinase activity
	neuregulin beta 1 receptor, high affinity
	regulates cell proliferation and differentiation
	involved in the regulation of the timing of astrogenesis in developing brain
	required for mammary gland development and lactation
	causes reversal regulation of PPP2R4 in the Shc signal transduction pathway in cancer cells
	NRG1/ERBB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex
	controls the development of inhibitory circuitries in the cerebral cortex by cell-autonomously regulating the connectivity of specific GABA-containing interneurons
	in the fetal lung, ERBB4 functions as a transcriptional regulator for surfactant protein B (SFPTB), the most critical surfactant protein gene
	directly regulates important aspects of fetal lung maturation that help prepare for the fetal-neonatal transition
	ERBB4 signaling modulates potentially proliferation and polarization, cellular functions critical for the development of epithelial ducts in the kidney
	plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes
	receptor tyrosine kinase implicated in the development and homeostasis of the heart, central nervous system, and mammary gland
	new role for NRG1/ERBB4 signaling in regulating oligodendrocyte precursors migration selectively during early stages of CNS development
	in the fetal lung, functions as a transcriptional co-factor and regulates the timely onset of fetal SFTP expression
	is a critical upstream regulator of TTF1 in type II epithelial cells and that this interaction is important for SFTPB regulation

CELLULAR PROCESS	cell life, differentiation
	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

development , nervous system

PATHWAY

metabolism

signaling

a component	part of a ternary complex made of one DLG4 and two ERBB4
	homodimer or heterodimer with each of the other ERBB receptors

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	related membrane-associated guanylate kinases
	SNT2B1
	SNT2B2
	interacting with NRG1, NRG2, NRG3
	NRG/ERBB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of DTNA
	directly activates STAT5A (phosphorylation of STAT5A are obligatory events regulating ERBB4-mediated activation of STAT5A)
	BTC acts via both the EGF receptor, located on Neural stem cells (NSCs), and ERBB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself
	NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers
	direct regulator of hypoxia-inducible factor-1A (HIF1A) signaling
	PIAS3 is a novel interaction partner of ERBB4 soluble intracellular domain (ICD)
	CADM1 interacts with ERBB4 and regulates the development of excitatory synapses via the regulation of ERBB4 activity in GABAergic neurons
	ERBB4 is an upstream regulator of TTF1 and regulates SFTPB expression via this pathway in alveolar type II cells
	BTC binds and activates EGFR and ERBB4 homodimers
	PTPN21 exerts pro-neuronal survival and neuritic elongation via ERBB4/NRG3 signaling

cell & other

REGULATION

activated by

NRG1, NRG3, NRG2

inhibited by

WWP1 in breast cancer

Other	cleaved by metalloprotease after ligand binding
	regulated by N-glycosylation that controls ErbB signaling by various mechanisms

ASSOCIATED DISORDERS

corresponding disease(s)

ALS19

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral germinal mutation       juxtamembrane splice variants in same chidhood medulloblastoma tumoral     --over   in lung carcinoma tumoral somatic mutation       in melanoma

Susceptibility

to schizophrenia to left ventricular outflow tract (LVOT) defects

Variant & Polymorphism other	interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia
	a specific haplotype in intron 3 of ERBB4 positively associated with the combined LVOT defects phenotype

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer skin   targeting of ERBB4 with small-molecule inhibitors should be considered as a therapeutic approach for the many individuals with melanoma

ANIMAL & CELL MODELS

astrogenesis occurs precociously in ErbB4 knock-out mice