Human Gene ERBB3 (ENST00000415288.6) Description and Page Index
  Description: Binds and is activated by neuregulins and NTAK. (from UniProt P21860)
RefSeq Summary (NM_001982): This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008].
Gencode Transcript: ENST00000415288.6
Gencode Gene: ENSG00000065361.15
Transcript (Including UTRs)
   Position: hg38 chr12:56,083,319-56,102,336 Size: 19,018 Total Exon Count: 29 Strand: +
Coding Region
   Position: hg38 chr12:56,083,846-56,102,055 Size: 18,210 Coding Exon Count: 27 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated: 2019-09-04

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr12:56,083,319-56,102,336)mRNA (may differ from genome)Protein (1283 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaBioGPS
MGIneXtProtPubMedReactomeStanford SOURCEUniProtKB

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Receptor tyrosine-protein kinase erbB-3; EC=; AltName: Full=Proto-oncogene-like protein c-ErbB-3; AltName: Full=Tyrosine kinase-type cell surface receptor HER3; Flags: Precursor;
FUNCTION: Binds and is activated by neuregulins and NTAK.
CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SUBUNIT: Monomer and homodimer. Heterodimer with each of the other ERBB receptors (Potential). Interacts with CSPG5, PA2G4, GRB7 and MUC1.
INTERACTION: P00533:EGFR; NbExp=6; IntAct=EBI-720706, EBI-297353; P04626:ERBB2; NbExp=15; IntAct=EBI-720706, EBI-641062; Q15303:ERBB4; NbExp=4; IntAct=EBI-720706, EBI-80371; Q02297-7:NRG1; NbExp=3; IntAct=EBI-720706, EBI-2460927; P27986:PIK3R1; NbExp=23; IntAct=EBI-720706, EBI-79464;
SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I membrane protein.
SUBCELLULAR LOCATION: Isoform 2: Secreted.
TISSUE SPECIFICITY: Epithelial tissues and brain.
DEVELOPMENTAL STAGE: Overexpressed in a subset of human mammary tumors.
DOMAIN: The cytoplasmic part of the receptor may interact with the SH2 or SH3 domains of many signal-transducing proteins.
PTM: Ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase (By similarity). Subject to autophosphorylation.
DISEASE: Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.
SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.
SIMILARITY: Contains 1 protein kinase domain.

-  MalaCards Disease Associations
  MalaCards Gene Search: ERBB3
Diseases sorted by gene-association score: lethal congenital contractural syndrome 2* (1365), retroperitoneal leiomyosarcoma (22), ovary transitional cell carcinoma (16), lethal congenital contracture syndrome (15), childhood medulloblastoma (13), gestational trophoblastic tumor (11), clear cell sarcoma (9), bartholin's gland benign neoplasm (9), breast cancer (8), charcot-marie-tooth disease, type 1a (7), lung cancer (7), neurogenic bladder (7), keratoconjunctivitis sicca (6), luminal breast carcinoma (5), pilocytic astrocytoma (5), mesenteric lymphadenitis (5), breast abscess (5), appendix adenocarcinoma (4), palindromic rheumatism (4), ovarian cancer, somatic (2), pancreatic cancer (2), colorectal cancer (2), prostate cancer (2), lung cancer susceptibility 3 (1), squamous cell carcinoma, head and neck (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 39.60 RPKM in Nerve - Tibial
Total median expression: 459.70 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -57.40220-0.261 Picture PostScript Text
3' UTR -61.40281-0.219 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR000494 - EGF_rcpt_L
IPR006211 - Furin-like_Cys-rich_dom
IPR006212 - Furin_repeat
IPR009030 - Growth_fac_rcpt
IPR011009 - Kinase-like_dom
IPR000719 - Prot_kinase_cat_dom
IPR001245 - Ser-Thr/Tyr_kinase_cat_dom
IPR020635 - Tyr_kinase_cat_dom
IPR016245 - Tyr_kinase_EGF/ERB/XmrK_rcpt

Pfam Domains:
PF00757 - Furin-like cysteine rich region
PF07714 - Protein tyrosine kinase
PF01030 - Receptor L domain

Protein Data Bank (PDB) 3-D Structure
MuPIT help

- X-ray MuPIT


- X-ray MuPIT
To conserve bandwidth, only the images from the first 3 structures are shown.
3LMG - X-ray MuPIT 3P11 - X-ray MuPIT

ModBase Predicted Comparative 3D Structure on P21860
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
Protein SequenceProtein Sequence    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0004672 protein kinase activity
GO:0004713 protein tyrosine kinase activity
GO:0004888 transmembrane signaling receptor activity
GO:0005088 Ras guanyl-nucleotide exchange factor activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0016301 kinase activity
GO:0016740 transferase activity
GO:0019838 growth factor binding
GO:0030296 protein tyrosine kinase activator activity
GO:0031625 ubiquitin protein ligase binding
GO:0038132 neuregulin binding
GO:0042802 identical protein binding
GO:0042803 protein homodimerization activity
GO:0046934 phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046982 protein heterodimerization activity

Biological Process:
GO:0000165 MAPK cascade
GO:0003197 endocardial cushion development
GO:0006468 protein phosphorylation
GO:0007162 negative regulation of cell adhesion
GO:0007165 signal transduction
GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007422 peripheral nervous system development
GO:0007507 heart development
GO:0009968 negative regulation of signal transduction
GO:0010628 positive regulation of gene expression
GO:0014037 Schwann cell differentiation
GO:0014065 phosphatidylinositol 3-kinase signaling
GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling
GO:0016310 phosphorylation
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0021545 cranial nerve development
GO:0038128 ERBB2 signaling pathway
GO:0042060 wound healing
GO:0042127 regulation of cell proliferation
GO:0043524 negative regulation of neuron apoptotic process
GO:0046854 phosphatidylinositol phosphorylation
GO:0051048 negative regulation of secretion
GO:0051402 neuron apoptotic process
GO:0051897 positive regulation of protein kinase B signaling
GO:0055025 positive regulation of cardiac muscle tissue development
GO:0061098 positive regulation of protein tyrosine kinase activity
GO:0070886 positive regulation of calcineurin-NFAT signaling cascade
GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand
GO:2000145 regulation of cell motility

Cellular Component:
GO:0005576 extracellular region
GO:0005615 extracellular space
GO:0005622 intracellular
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0016323 basolateral plasma membrane
GO:0016324 apical plasma membrane
GO:0016328 lateral plasma membrane
GO:0043235 receptor complex

-  Descriptions from all associated GenBank mRNAs
  M34309 - Human epidermal growth factor receptor (HER3) mRNA, complete cds.
AK300909 - Homo sapiens cDNA FLJ53210 complete cds, highly similar to Receptor tyrosine-protein kinase erbB-3 precursor (EC
AK294719 - Homo sapiens cDNA FLJ59207 complete cds, highly similar to Receptor tyrosine-protein kinase erbB-3 precursor (EC
AK291681 - Homo sapiens cDNA FLJ76884 complete cds, highly similar to Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) (ERBB3), transcript variant 1, mRNA.
BC082992 - Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian), mRNA (cDNA clone MGC:88033 IMAGE:6147464), complete cds.
M29366 - Human epidermal growth factor receptor (ERBB3) mRNA, complete cds.
BC002706 - Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian), mRNA (cDNA clone IMAGE:3629646), complete cds.
LF213765 - JP 2014500723-A/21268: Polycomb-Associated Non-Coding RNAs.
MA449342 - JP 2018138019-A/21268: Polycomb-Associated Non-Coding RNAs.
AK295650 - Homo sapiens cDNA FLJ55330 complete cds, highly similar to Receptor tyrosine-protein kinase erbB-3 precursor (EC
BC041579 - Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian), mRNA (cDNA clone IMAGE:4645144).
AK124710 - Homo sapiens cDNA FLJ42720 fis, clone BRAMY4000095, highly similar to Receptor tyrosine-protein kinase erbB-3 precursor (EC
AK125028 - Homo sapiens cDNA FLJ43038 fis, clone BRTHA3002955, highly similar to Receptor tyrosine-protein kinase erbB-3 precursor (EC
S61953 - c-erbB3=receptor tyrosine kinase {alternatively spliced} [human, gastric cancer cell line MNK45, mRNA, 1042 nt].
CU678138 - Synthetic construct Homo sapiens gateway clone IMAGE:100018975 5' read ERBB3 mRNA.
KJ901412 - Synthetic construct Homo sapiens clone ccsbBroadEn_10806 ERBB3 gene, encodes complete protein.
BT007226 - Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) mRNA, complete cds.
CQ873790 - Sequence 209 from Patent WO2004076622.
DD413627 - Regulation of Mammalian Cells.
U88357 - Homo sapiens clone R1 ErbB-3 R1 (c-erbB-3) mRNA, partial cds.
U88358 - Homo sapiens clone R2 ErbB-3 R2 (c-erbB-3) mRNA, partial cds.
U88360 - Homo sapiens clone R35 ErbB-3 R35 (c-erbB-3) mRNA, partial cds.
U88359 - Homo sapiens clone R31 ErbB-3 R31 (c-erbB-3) mRNA, partial cds.
LF208962 - JP 2014500723-A/16465: Polycomb-Associated Non-Coding RNAs.
MA444539 - JP 2018138019-A/16465: Polycomb-Associated Non-Coding RNAs.
LF324492 - JP 2014500723-A/131995: Polycomb-Associated Non-Coding RNAs.
MA560069 - JP 2018138019-A/131995: Polycomb-Associated Non-Coding RNAs.
LF324491 - JP 2014500723-A/131994: Polycomb-Associated Non-Coding RNAs.
MA560068 - JP 2018138019-A/131994: Polycomb-Associated Non-Coding RNAs.
JD325211 - Sequence 306235 from Patent EP1572962.
JD219245 - Sequence 200269 from Patent EP1572962.
JD224497 - Sequence 205521 from Patent EP1572962.
JD239968 - Sequence 220992 from Patent EP1572962.
JD056461 - Sequence 37485 from Patent EP1572962.
JD487464 - Sequence 468488 from Patent EP1572962.
JD387498 - Sequence 368522 from Patent EP1572962.
JD166833 - Sequence 147857 from Patent EP1572962.
JD120022 - Sequence 101046 from Patent EP1572962.
JD556532 - Sequence 537556 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04012 - ErbB signaling pathway
hsa04020 - Calcium signaling pathway
hsa04144 - Endocytosis

BioCarta from NCI Cancer Genome Anatomy Project
h_ErbB3Pathway - Neuroregulin receptor degredation protein-1 Controls ErbB3 receptor recycling
h_her2Pathway - Role of ERBB2 in Signal Transduction and Oncology

Reactome (by CSHL, EBI, and GO)

Protein P21860 (Reactome details) participates in the following event(s):

R-HSA-1247497 ERBB3 binds neuregulins
R-HSA-1358801 ERBB3 binds RNF41 ubiquitin ligase
R-HSA-1977958 ERBB4 forms heterodimers with ERBB3
R-HSA-1358790 RNF41 ubiquitinates ERBB3
R-HSA-1963589 ERBB2 forms heterodimers with ligand-activated ERBB receptors: EGFR, ERBB3 and ERBB4
R-HSA-1963582 Trans-autophosphorylation of ERBB2 heterodimers
R-HSA-1963586 SRC family kinases phosphorylate ERBB2
R-HSA-1963581 Trans-autophosphorylation of p-Y877-ERBB2 heterodimers
R-NUL-1248753 Shc1 binds phosphorylated ERBB2:ERBB3 heterodimers
R-HSA-1250189 Binding of PI3K to ERBB2:P-ERBB3 heterodimer
R-HSA-1306953 GRB7 binds phosphorylated heterodimer of ERBB2 and ERBB3
R-HSA-1358798 RNF41 binds neuregulin-activated ERBB3
R-HSA-1963563 MATK (CSK homologous kinase) binds phosphorylated ERBB2
R-HSA-1963578 SHC1 binds phosphorylated ERBB2 heterodimers
R-HSA-6785636 Phosphorylated ERBB2 heterodimers bind MEMO1
R-HSA-8847995 Activated ERBB2 binds PTK6 (BRK)
R-HSA-8863804 PTPN12 dephosphorylates ERBB2 on tyrosine Y1248
R-HSA-8848005 ERBB2 promotes PTK6 autophosphorylation
R-HSA-1358792 RNF41 ubiquitinates activated ERBB3
R-HSA-1250195 SHC1 phosphorylation by ERBB2 heterodimers
R-HSA-1250486 Recruitment of GRB2:SOS1 to p-SHC1 in complex with phosphorylated ERBB2 heterodimers
R-HSA-6785648 MEMO1 binds RHOA:GTP:DIAPH1
R-HSA-1250462 PIP2 to PIP3 conversion by PI3K bound to phosphorylated heterodimer of ERBB2 and ERBB3
R-HSA-1250463 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-SHC1:Phosphorylated ERBB2 heterodimers
R-HSA-2400009 PI3K inhibitors block PI3K catalytic activity
R-HSA-2316434 PI3K phosphorylates PIP2 to PIP3
R-HSA-5672965 RAS GEFs promote RAS nucleotide exchange
R-HSA-1227986 Signaling by ERBB2
R-HSA-1358803 Downregulation of ERBB2:ERBB3 signaling
R-HSA-1236394 Signaling by ERBB4
R-HSA-9006934 Signaling by Receptor Tyrosine Kinases
R-HSA-8863795 Downregulation of ERBB2 signaling
R-HSA-162582 Signal Transduction
R-HSA-1963642 PI3K events in ERBB2 signaling
R-HSA-1306955 GRB7 events in ERBB2 signaling
R-HSA-1250196 SHC1 events in ERBB2 signaling
R-HSA-6785631 ERBB2 Regulates Cell Motility
R-HSA-8847993 ERBB2 Activates PTK6 Signaling
R-HSA-8848021 Signaling by PTK6
R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-2219528 PI3K/AKT Signaling in Cancer
R-HSA-9006925 Intracellular signaling by second messengers
R-HSA-199418 Negative regulation of the PI3K/AKT network
R-HSA-5684996 MAPK1/MAPK3 signaling
R-HSA-5663202 Diseases of signal transduction
R-HSA-5683057 MAPK family signaling cascades
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: A8K6L6, AK295650, B4DIK7, B4DV32, E9PDT8, ERBB3_HUMAN, HER3, P21860, Q9BUD7, uc010sqc.1, uc010sqc.2, uc010sqc.3
UCSC ID: uc010sqc.3
RefSeq Accession: NM_001982
Protein: P21860 (aka ERBB3_HUMAN)
CCDS: CCDS31833.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.