ERBB4

Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene.^[5][6] Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.^[7]

ERBB4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2AHX, 2L2T, 2LCX, 2R4B, 3BBT, 3BBW, 3BCE, 3U2P, 3U7U, 3U9U
Identifiers
Aliases	ERBB4, ALS19, HER4, p180erbB4, erb-b2 receptor tyrosine kinase 4
External IDs	OMIM: 600543; MGI: 104771; HomoloGene: 21084; GeneCards: ERBB4; OMA:ERBB4 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q34 Start 211,375,717 bp[1] End 212,538,841 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 C3|1 33.8 cM Start 68,071,345 bp[2] End 69,147,218 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell secondary oocyte optic nerve middle temporal gyrus buccal mucosa cell Brodmann area 23 entorhinal cortex Brodmann area 46 orbitofrontal cortex right uterine tube Top expressed in dentate gyrus of hippocampal formation granule cell superior frontal gyrus interventricular septum visual cortex primary visual cortex Cardiac muscle tissue of myocardium cardiac muscle tissue of left ventricle corneal stroma plantaris muscle gray matter layer of cerebellum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity protein homodimerization activity epidermal growth factor receptor binding kinase activity protein binding transmembrane receptor protein tyrosine kinase activity ATP binding protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity receptor tyrosine kinase transmembrane signaling receptor activity Cellular component integral component of membrane cytosol membrane receptor complex plasma membrane nucleoplasm extracellular region mitochondrial matrix basolateral plasma membrane mitochondrion nucleus postsynaptic membrane glutamatergic synapse GABA-ergic synapse integral component of presynaptic membrane integral component of postsynaptic density membrane cytoplasm integral component of plasma membrane basal plasma membrane Biological process mitochondrial fragmentation involved in apoptotic process negative regulation of neuron migration cell fate commitment positive regulation of protein phosphorylation regulation of cell migration regulation of transcription, DNA-templated olfactory bulb interneuron differentiation embryonic pattern specification phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway central nervous system morphogenesis mammary gland alveolus development transcription, DNA-templated nervous system development mammary gland epithelial cell differentiation MAPK cascade positive regulation of phosphatidylinositol 3-kinase activity positive regulation of transcription, DNA-templated multicellular organism development heart development protein phosphorylation positive regulation of cardiac muscle cell proliferation neural crest cell migration positive regulation of ERK1 and ERK2 cascade positive regulation of protein localization to cell surface protein autophosphorylation cardiac muscle tissue regeneration positive regulation of phosphatidylinositol 3-kinase signaling peptidyl-tyrosine phosphorylation lactation cell population proliferation cell migration signal transduction negative regulation of cell population proliferation apoptotic process ERBB2 signaling pathway phosphatidylinositol phosphate biosynthetic process peptidyl-tyrosine autophosphorylation positive regulation of cell population proliferation positive regulation of apoptotic process regulation of cell motility negative regulation of apoptotic process cellular response to epidermal growth factor stimulus positive regulation of tyrosine phosphorylation of STAT protein positive regulation of protein kinase B signaling positive regulation of receptor signaling pathway via JAK-STAT synapse assembly negative regulation of signal transduction cell differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2066 13869 Ensembl ENSG00000178568 ENSMUSG00000062209 UniProt Q15303 Q61527 RefSeq (mRNA) NM_001042599 NM_005235 NM_010154 RefSeq (protein) NP_001036064 NP_005226 NP_034284 Location (UCSC) Chr 2: 211.38 – 212.54 Mb Chr 1: 68.07 – 69.15 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Receptor tyrosine-protein kinase erbB-4 is a receptor tyrosine kinase that is a member of the epidermal growth factor receptor family. ERBB4 is a single-pass type I transmembrane protein with multiple furin-like cysteine rich domains, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins-2, -3 and -4, heparin-binding EGF-like growth factor and betacellulin. Ligand binding induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment.^[7]

Clinical significance

Mutations in this gene have been associated with cancer.^[7] Other single-nucleotide polymorphisms and a risk haplotype have been linked to schizophrenia.^[8] Single-nucleotide polymorphisms in ERBB4 have also been found in a study of patients with familial amyotrophic lateral sclerosis type 19.^[9]

Interactions

ERBB4 has been shown to interact with:

• DLG4^[10][11]
• NRG1,
• STAT5A,^[12][13] and
• YAP1.^[14]

References

1. GRCh38: Ensembl release 89: ENSG00000178568 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000062209 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Zimonjic DB, Alimandi M, Miki T, Popescu NC, Kraus MH (Mar 1995). "Localization of the human HER4/erbB-4 gene to chromosome 2". Oncogene. 10 (6): 1235–7. PMID 7700649.
6. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G (Oct 2006). "Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain". Cell. 127 (1): 185–97. doi:10.1016/j.cell.2006.07.037. PMID 17018285. S2CID 18779079.
7. "Entrez Gene: ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)".
8. Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R (Mar 2006). "The involvement of ErbB4 with schizophrenia: association and expression studies". American Journal of Medical Genetics Part B. 141B (2): 142–8. doi:10.1002/ajmg.b.30275. PMID 16402353. S2CID 23553550.
9. Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, et al. (Nov 2013). "ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19". American Journal of Human Genetics. 93 (5): 900–5. doi:10.1016/j.ajhg.2013.09.008. PMC 3824132. PMID 24119685.
10. Garcia RA, Vasudevan K, Buonanno A (Mar 2000). "The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3596–601. doi:10.1073/pnas.070042497. PMC 16285. PMID 10725395.
11. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L (May 2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron. 26 (2): 443–55. doi:10.1016/S0896-6273(00)81176-9. PMID 10839362. S2CID 1429113.
12. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE (Nov 2004). "The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone". The Journal of Cell Biology. 167 (3): 469–78. doi:10.1083/jcb.200403155. PMC 2172499. PMID 15534001.
13. Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Molecular Systems Biology. 1 (1): 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
14. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M (Apr 2004). "Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level". Experimental Cell Research. 294 (2): 469–79. doi:10.1016/j.yexcr.2003.12.002. PMID 15023535.

Further reading

• Carpenter G (Mar 2003). "ErbB-4: mechanism of action and biology". Experimental Cell Research. 284 (1): 66–77. doi:10.1016/S0014-4827(02)00100-3. PMID 12648466.
• Culouscou JM, Plowman GD, Carlton GW, Green JM, Shoyab M (Sep 1993). "Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor". The Journal of Biological Chemistry. 268 (25): 18407–10. doi:10.1016/S0021-9258(17)46636-1. PMID 7689552.
• Barbacci EG, Guarino BC, Stroh JG, Singleton DH, Rosnack KJ, Moyer JD, Andrews GC (Apr 1995). "The structural basis for the specificity of epidermal growth factor and heregulin binding". The Journal of Biological Chemistry. 270 (16): 9585–9. doi:10.1074/jbc.270.16.9585. PMID 7721889.
• Nagata K, Kohda D, Hatanaka H, Ichikawa S, Matsuda S, Yamamoto T, Suzuki A, Inagaki F (Aug 1994). "Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4". The EMBO Journal. 13 (15): 3517–23. doi:10.1002/j.1460-2075.1994.tb06658.x. PMC 395255. PMID 8062828.
• Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M (Mar 1993). "Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family". Proceedings of the National Academy of Sciences of the United States of America. 90 (5): 1746–50. Bibcode:1993PNAS...90.1746P. doi:10.1073/pnas.90.5.1746. PMC 45956. PMID 8383326.
• Cohen BD, Green JM, Foy L, Fell HP (Mar 1996). "HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers". The Journal of Biological Chemistry. 271 (9): 4813–8. doi:10.1074/jbc.271.9.4813. PMID 8617750.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Elenius K, Paul S, Allison G, Sun J, Klagsbrun M (Mar 1997). "Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation". The EMBO Journal. 16 (6): 1268–78. doi:10.1093/emboj/16.6.1268. PMC 1169725. PMID 9135143.
• Chang H, Riese DJ, Gilbert W, Stern DF, McMahan UJ (May 1997). "Ligands for ErbB-family receptors encoded by a neuregulin-like gene". Nature. 387 (6632): 509–12. Bibcode:1997Natur.387R.509C. doi:10.1038/387509a0. PMID 9168114. S2CID 4359654.
• Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C (May 1997). "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases". Nature. 387 (6632): 512–6. Bibcode:1997Natur.387R.512C. doi:10.1038/387512a0. PMID 9168115. S2CID 4310136.
• Chow NH, Liu HS, Yang HB, Chan SH, Su IJ (Jun 1997). "Expression patterns of erbB receptor family in normal urothelium and transitional cell carcinoma. An immunohistochemical study". Virchows Archiv. 430 (6): 461–6. doi:10.1007/s004280050056. PMID 9230911. S2CID 35461038.
• Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ (Sep 1997). "Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4". Proceedings of the National Academy of Sciences of the United States of America. 94 (18): 9562–7. Bibcode:1997PNAS...94.9562Z. doi:10.1073/pnas.94.18.9562. PMC 23218. PMID 9275162.
• Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD, Klagsbrun M (Oct 1997). "A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester". The Journal of Biological Chemistry. 272 (42): 26761–8. doi:10.1074/jbc.272.42.26761. PMID 9334263.
• Komurasaki T, Toyoda H, Uchida D, Morimoto S (1997). "Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4". Oncogene. 15 (23): 2841–8. doi:10.1038/sj.onc.1201458. PMID 9419975. S2CID 32124103.
• Fiddes RJ, Campbell DH, Janes PW, Sivertsen SP, Sasaki H, Wallasch C, Daly RJ (Mar 1998). "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3". The Journal of Biological Chemistry. 273 (13): 7717–24. doi:10.1074/jbc.273.13.7717. PMID 9516479.
• Jones JT, Ballinger MD, Pisacane PI, Lofgren JA, Fitzpatrick VD, Fairbrother WJ, Wells JA, Sliwkowski MX (May 1998). "Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis". The Journal of Biological Chemistry. 273 (19): 11667–74. doi:10.1074/jbc.273.19.11667. PMID 9565587.
• Srinivasan R, Poulsom R, Hurst HC, Gullick WJ (Jul 1998). "Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types". The Journal of Pathology. 185 (3): 236–45. doi:10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7. PMID 9771476. S2CID 23117095.
• Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y (Apr 1999). "Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase". Oncogene. 18 (17): 2681–9. doi:10.1038/sj.onc.1202631. PMID 10348342. S2CID 25901713.

External links

• Overview of all the structural information available in the PDB for UniProt: Q15303 (Receptor tyrosine-protein kinase erbB-4) at the PDBe-KB.