ERBB4

V-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)
PDB rendering based on 2ahx.
Available structures PDB 2AHX, 2R4B, 3BBT, 3BBW, 3BCE
Identifiers
Symbols	ERBB4; HER4; MGC138404; p180erbB4
External IDs	OMIM: 600543 MGI: 104771 HomoloGene: 21084 GeneCards: ERBB4 Gene
EC number	2.7.10.1
Gene Ontology Molecular function • nucleotide binding • transmembrane receptor protein tyrosine kinase activity • receptor signaling protein tyrosine kinase activity • receptor activity • protein binding • ATP binding Cellular component • nucleus • nucleolus • cytoplasm • plasma membrane • caveola • postsynaptic density • integral to membrane • basolateral plasma membrane Biological process • regulation of transcription, DNA-dependent • signal transduction • transmembrane receptor protein tyrosine kinase signaling pathway • heart development • cell proliferation • telencephalon development • positive regulation of cell migration • mammary gland development • positive regulation of synaptic transmission, GABAergic • response to progesterone stimulus • odontogenesis • response to drug • response to hydrogen peroxide • surfactant homeostasis • cell fate commitment • positive regulation of anti-apoptosis • positive regulation of glucose import • positive regulation of epithelial cell proliferation • synapse maturation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2066	13869
Ensembl	ENSG00000178568	ENSMUSG00000062209
UniProt	Q15303	O88459
RefSeq (mRNA)	NM_001042599.1	NM_010154.1
RefSeq (protein)	NP_001036064.1	NP_034284.1
Location (UCSC)	Chr 2: 212.24 – 213.4 Mb	Chr 1: 68.08 – 69.15 Mb
PubMed search	[1]	[2]

Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene.^[1][2] Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.^[3]

Function

Receptor tyrosine-protein kinase erbB-4 is a receptor tyrosine kinase that is a member of the epidermal growth factor receptor subfamily. 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 and -3, 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.^[3]

Clinical significance

Mutations in this gene have been associated with cancer.^[3] Other single-nucleotide polymorphisms and a risk haplotype have been linked to schizophrenia.^[4]

Interactions

ERBB4 has been shown to interact with:

• DLG4^[5][6]
• NRG1,
• STAT5A,^[7][8] and
• YAP1.^[9]

References

1. ^ Zimonjic DB, Alimandi M, Miki T, Popescu NC, Kraus MH (May 1995). "Localization of the human HER4/erbB-4 gene to chromosome 2". Oncogene 10 (6): 1235–7. PMID 7700649. 
2. ^ 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. 
3. ^ ^{a b c} "Entrez Gene: ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2066. 
4. ^ Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R (2006). "The involvement of ErbB4 with schizophrenia: association and expression studies". Am J Med Genet B Neuropsychiatr Genet 141 (B2): 142–8. doi:10.1002/ajmg.b.30275. PMID 16402353. 
5. ^ Garcia, R A; Vasudevan K, Buonanno A (Mar. 2000). "The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 97 (7): 3596–601. doi:10.1073/pnas.070042497. ISSN 0027-8424. PMC 16285. PMID 10725395. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=16285. 
6. ^ Huang, Y Z; Won S, Ali D W, Wang Q, Tanowitz M, Du Q S, Pelkey K A, Yang D J, Xiong W C, Salter M W, Mei L (May. 2000). "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron (UNITED STATES) 26 (2): 443–55. doi:10.1016/S0896-6273(00)81176-9. ISSN 0896-6273. PMID 10839362. 
7. ^ Williams, Christopher C; Allison June G, Vidal Gregory A, Burow Matthew E, Beckman Barbara S, Marrero Luis, Jones Frank E (Nov. 2004). "The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone". J. Cell Biol. (United States) 167 (3): 469–78. doi:10.1083/jcb.200403155. ISSN 0021-9525. PMC 2172499. PMID 15534001. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2172499. 
8. ^ Schulze, Waltraud X; Deng Lei, Mann Matthias (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. (England) 1 (1): 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1681463. 
9. ^ Omerovic, Jasminka; Puggioni Eleonora M R, Napoletano Silvia, Visco Vincenzo, Fraioli Rocco, Frati Luigi, Gulino Alberto, Alimandi Maurizio (Apr. 2004). "Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level". Exp. Cell Res. (United States) 294 (2): 469–79. doi:10.1016/j.yexcr.2003.12.002. ISSN 0014-4827. PMID 15023535. 

Further reading

• Carpenter G (2003). "ErbB-4: mechanism of action and biology". Exp. Cell Res. 284 (1): 66–77. doi:10.1016/S0014-4827(02)00100-3. PMID 12648466. 
• Culouscou JM, Plowman GD, Carlton GW et al. (1993). "Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor". J. Biol. Chem. 268 (25): 18407–10. PMID 7689552. 
• Barbacci EG, Guarino BC, Stroh JG et al. (1995). "The structural basis for the specificity of epidermal growth factor and heregulin binding". J. Biol. Chem. 270 (16): 9585–9. doi:10.1074/jbc.270.16.9585. PMID 7721889. 
• Nagata K, Kohda D, Hatanaka H et al. (1994). "Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4". EMBO J. 13 (15): 3517–23. PMC 395255. PMID 8062828. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=395255. 
• Plowman GD, Culouscou JM, Whitney GS et al. (1993). "Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family". Proc. Natl. Acad. Sci. U.S.A. 90 (5): 1746–50. doi:10.1073/pnas.90.5.1746. PMC 45956. PMID 8383326. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=45956. 
• Cohen BD, Green JM, Foy L, Fell HP (1996). "HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers". J. Biol. Chem. 271 (9): 4813–8. doi:10.1074/jbc.271.9.4813. PMID 8617750. 
• Andersson B, Wentland MA, Ricafrente JY et al. (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474. 
• Yu W, Andersson B, Worley KC et al. (1997). "Large-Scale Concatenation cDNA Sequencing". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139146. 
• Elenius K, Paul S, Allison G et al. (1997). "Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation". EMBO J. 16 (6): 1268–78. doi:10.1093/emboj/16.6.1268. PMC 1169725. PMID 9135143. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1169725. 
• Chang H, Riese DJ, Gilbert W et al. (1997). "Ligands for ErbB-family receptors encoded by a neuregulin-like gene". Nature 387 (6632): 509–12. doi:10.1038/387509a0. PMID 9168114. 
• Carraway KL, Weber JL, Unger MJ et al. (1997). "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases". Nature 387 (6632): 512–6. doi:10.1038/387512a0. PMID 9168115. 
• Chow NH, Liu HS, Yang HB et al. (1997). "Expression patterns of erbB receptor family in normal urothelium and transitional cell carcinoma. An immunohistochemical study". Virchows Arch. 430 (6): 461–6. doi:10.1007/s004280050056. PMID 9230911. 
• Zhang D, Sliwkowski MX, Mark M et al. (1997). "Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4". Proc. Natl. Acad. Sci. U.S.A. 94 (18): 9562–7. doi:10.1073/pnas.94.18.9562. PMC 23218. PMID 9275162. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=23218. 
• Elenius K, Corfas G, Paul S et al. (1997). "A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester". J. Biol. Chem. 272 (42): 26761–8. doi:10.1074/jbc.272.42.26761. PMID 9334263. 
• Komurasaki T, Toyoda H, Uchida D, Morimoto S (1998). "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. 
• Fiddes RJ, Campbell DH, Janes PW et al. (1998). "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3". J. Biol. Chem. 273 (13): 7717–24. doi:10.1074/jbc.273.13.7717. PMID 9516479. 
• Jones JT, Ballinger MD, Pisacane PI et al. (1998). "Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis". J. Biol. Chem. 273 (19): 11667–74. doi:10.1074/jbc.273.19.11667. PMID 9565587. 
• Srinivasan R, Poulsom R, Hurst HC, Gullick WJ (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". J. Pathol. 185 (3): 236–45. doi:10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7. PMID 9771476. 
• Harari D, Tzahar E, Romano J et al. (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.