ERBB4 explained

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 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.^[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] Single-nucleotide polymorphisms in ERBB4 have also been found in a study of patients with familial amyotrophic lateral sclerosis type 19.^[5]

Interactions

ERBB4 has been shown to interact with:

• DLG4^{[6] [7]}
• NRG1,
• STAT5A,^{[8] [9]} and
• YAP1.^[10]

Further reading

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

Notes and References

1. Zimonjic DB, Alimandi M, Miki T, Popescu NC, Kraus MH . Localization of the human HER4/erbB-4 gene to chromosome 2 . Oncogene . 10 . 6 . 1235–7 . Mar 1995 . 7700649 .
2. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G . Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain . Cell . 127 . 1 . 185–97 . Oct 2006 . 17018285 . 10.1016/j.cell.2006.07.037 . 18779079 . free .
3. Web site: Entrez Gene: ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian).
4. Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R . The involvement of ErbB4 with schizophrenia: association and expression studies . American Journal of Medical Genetics Part B . 141B . 2 . 142–8 . Mar 2006 . 16402353 . 10.1002/ajmg.b.30275 . 23553550 .
5. Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, Belzil VV, Dion PA, Higasa K, Doi K, Ishiura H, Mitsui J, Date H, Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T, Ikoma M, Hashimoto T, Kimura F, Murayama S, Onodera O, Nishizawa M, Yoshida M, Atsuta N, Sobue G, Fifita JA, Williams KL, Blair IP, Nicholson GA, Gonzalez-Perez P, Brown RH, Nomoto M, Elenius K, Rouleau GA, Fujiyama A, Morishita S, Goto J, Tsuji S. 6 . ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19 . American Journal of Human Genetics . 93 . 5 . 900–5 . Nov 2013 . 24119685 . 3824132 . 10.1016/j.ajhg.2013.09.008 .
6. Garcia RA, Vasudevan K, Buonanno A . 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 . Mar 2000 . 10725395 . 16285 . 10.1073/pnas.070042497 . free .
7. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L . Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses . Neuron . 26 . 2 . 443–55 . May 2000 . 10839362 . 10.1016/S0896-6273(00)81176-9 . 1429113 . free .
8. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE . 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 . Nov 2004 . 15534001 . 2172499 . 10.1083/jcb.200403155 .
9. Schulze WX, Deng L, Mann M . Phosphotyrosine interactome of the ErbB-receptor kinase family . Molecular Systems Biology . 1 . 1 . 2005.0008 . 2005 . 16729043 . 1681463 . 10.1038/msb4100012 .
10. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M . 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 . Apr 2004 . 15023535 . 10.1016/j.yexcr.2003.12.002 .