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FLASH GENE

Symbol

ERBB3

contributors: mct/np/shn/pgu - updated : 20-06-2018

HGNC name	v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)
HGNC id	3431

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	LCCS2 lethal congenital contracture syndrome 2
Location	12q13.2      Physical location : 56.473.891 - 56.497.127
Synonym name	tyrosine kinase-type cell surface receptor
	lethal congenital contracture syndrome 2
	receptor tyrosine-protein kinase erbB-3 precursor
Synonym symbol(s)	HER3, ERB3, ErbB-3, c-erbB3, erbB3-S, MDA-BF-1, p180-ErbB3, p45-sErbB3, p85-sErbB3, MGC88033, LCCS2
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	23.24 kb     28 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

Map	cen - D12S1707 - D12S1632 - ERBB3 - D12S1644 - D12S1691 - qter

RNA

TRANSCRIPTS	type	messenger

text	additional splice variants have also been reported, but they have not been thoroughly characterized alternative transcription initiation results in the formation of a nuclear variant of ErbB3 (nuc-ErbB3) primary Schwann cells (PMID:21451047)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001982 28 splicing 5511 NP_001973 160 1342 cell membrane (single-pass type I membrane protein) 1990 2164210 a 19 aa peptide signal of 2 kda a 1323 aa mature peptide of 146.1 kda variant S NM_001005915 3 splicing 1050 NP_001005915 - 183 secreted protein 1993 7685162 modulating the activity of the membrane-bound form a 19 aa signal peptide of 2 kda a 164 aa mature peptide of 18.1 kda

EXPRESSION

Type

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         Digestive mouth       highly Hearing/Equilibrium ear inner cochlea   highly Nervous brain         Respiratory respiratory tract trachea     predominantly Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cell lineage
cell lines	mammary tumor MDA-MB415 and MDA-MB453 cell lines (
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a 19 aa signal peptide (2 kda)
	an extracellular cysteine-rich ligand binding domain (heparin-binding site)
	a single transmembrane (1TM) protein with extensive homology to the epidermal growth factor receptor, lacking the C terminal catalytic domain (kinase domain binds ATP, but is catalytically inactive and can serve as an activator of the EGFR kinase domain)
	a furin-like cystein rich region
	a tyrosine kinase catalytic domain
	specific N-glycan in domain III playing an essential role in regulating receptor dimerization and transforming activity
	a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645-657)) in the juxtamembrane region
	a functional nuclear localization signal sequence (

mono polymer

homomer , heteromer , dimer

isoforms

Precursor

a 1323 aa mature peptide of 146.1 kda

HOMOLOGY

interspecies	ortholog to ERBB3, Pan troglodytes
	ortholog to Erbb3, Rattus norvegicus
	ortholog to Erbb3, Mus musculus

intraspecies	homolog to viral (v-erb-b) oncogene 3
	homolog to IGF1R

Homologene

FAMILY

epidermal growth factor receptor (EGFR) subfamily

CATEGORY

enzyme , protooncogene , receptor membrane tyrosine kinase

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,nucleus
text	apical and lateral plasma membrane

basic FUNCTION	acting as a receptor tyrosine kinase
	acting as a neuregulin beta 1 receptor low affinity
	acting as an heregulin receptor
	acting as an epidermal growth factor receptor
	activator of the phosphatidylinositol-3-kinase/Akt pathway, regulating cell survival and vesicle trafficking, essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor
	neurons
	regulating PI3K/Akt pathway, a critical survival pathway in neurons and in most cell types, through heregulin
	contributes to tumorigenic conversion and that their expression levels may be increased by signaling initiated by TGF-alpha (
	ERBB3 signaling may contribute to metastatic progression of melanoma
	ERBB3 function is an important aspect of ERBB2-mediated breast cancer, prompting the need for a more thorough understanding of ERBB3 expression and dysregulation in breast cancer
	both ERBB3 and RNF41 are dysregulated post-transcriptionally in tumors
	functions in part, by modulating the activity of ERBB3
	plays an essential role in ERBB2-mediated transformation, tumor progression, and drug resistance
	regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine- and paracrine-signaling mechanisms
	is catalytically impaired but binds ligand, and its kinase domain allosterically activates its partners
	high levels of ERBB2, ERBB3 may not only be a target of constitutive phosphorylation and driver for enhanced cancer cell survival
	both ERBB2 and ERBB3 are essential for normal proliferation of skin keratinocytes, but in contrast to ERBB3, ERBB2 is essential for migration of human keratinocytes

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	heart development
	peripheral nervous system development

PATHWAY

metabolism

signaling

signal transduction

	transmembrane receptor protein tyrosine kinase signaling pathway
	PI3K/Akt pathway

a component	dimerizing with the ligand less receptor ERBB2
	heterodimerizing with ERBB2 for catalytic function
	heterodimerizing with each of the other ERBB receptors
	heterodimers of the ligand-binding–deficient ERBB2 (HER2) receptor and the kinase impaired ERBB3 (HER3) create a potent mitogenic signal

INTERACTION

DNA	chromatin (

RNA

small molecule	nucleotide,
	ATP

protein	neu differentiation factor, NDF (
	Neuregulin-2, NRG2 (
	p23/p198 (
	proliferation-associated 2G4, 38kDa, PA2G4 (
	angiotensin II receptor sub-type AT2 (
	focal adhesion kinase, FAK (
	Sos Ras exchange protein (
	gp130 (
	Epidermal growth factor, EGF (
	E3 ubiquitin-protein ligase NRDP1, NRDP1 (
	NTAK
	CSPG5
	associates with RNF41 which stimulates its ubiquitination and degradation by proteasomes
	regulator of G-protein signaling 4, RGS4 (
	Tetraspanin CD82 (
	v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), ERBB2 (
	sclerostin and the C-terminal portion of the receptor tyrosine-protein kinase ERBB3
	Neuregulin-1, NRG1 (
	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
	interaction of CADM1 with ERBB3 inhibits the NRG1-induced ERBB3/ERBB2 signaling in epithelial cells
	APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis

cell & other

REGULATION

activated by	NRG1, NRG2
	NTAK

Other	regulated expression by Sox10 during development of the neural crest
	phosphorylated ERBB3 is a particularly potent signaling molecule because it activates the PI3K/AKT pathway
	regulated by N-glycosylation that controls ErbB signaling by various mechanisms
	translation of nuclear variant of ErbB3 is regulated by Neuregulin-1 (

ASSOCIATED DISORDERS

corresponding disease(s)

LCCS2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in a subset of mammary tumors tumoral   amplification --over   amplification and/or overexpression reported in numerous cancers, including prostate, bladder, and breast tumors tumoral     --over   in pilocytic astrocytoma tumoral     --over   strongly associated with tumor progression and poor prognosis of patients with gastric cancer

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive breast therapeutic inhibitors of ERBB3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with ERBB2- and PI3K-dependent cancers cancer lung   small inhibitory RNA (siRNA) showing promise as a therapeutic approach to treatment of lung adenocarcinoma cancer skin   targeting ERBB3 activation and downstream genes may provide novel therapeutic interventions for malignant melanoma cancer digestive stomach new prognostic factor and a target of treatment in gastric cancer cancer reproductive breast ERBB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling

ANIMAL & CELL MODELS