The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Erbb4  -  v-erb-a erythroblastic leukemia viral...

Mus musculus

Synonyms: ErbB4, Her4, Mer4, Proto-oncogene-like protein c-ErbB-4, Receptor tyrosine-protein kinase erbB-4, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Erbb4


High impact information on Erbb4

  • Here we demonstrate that ErbB4 is an essential in vivo regulator of both cardiac muscle differentiation and axon guidance in the central nervous system (CNS) [6].
  • They also display striking alterations in innervation of the hindbrain in the CNS that are consistent with the restricted expression of the ErbB4 gene in rhombomeres 3 and 5 [6].
  • Mice lacking ErbB4 die during mid-embryogenesis from the aborted development of myocardial trabeculae in the heart ventricle [6].
  • Various in vitro studies have suggested that ErbB4 (HER4) is a receptor for the neuregulins, a family of closely related proteins implicated as regulators of neural and muscle development, and of the differentiation and oncogenic transformation of mammary epithelia [6].
  • Inhibition of gamma-secretase also prevented growth inhibition by HRG. gamma-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase-mediated signaling [7].

Biological context of Erbb4

  • Here, we show that mice with Cre-lox mediated deletions of both Erbb4 alleles within the developing mammary gland (Erbb4(Flox/Flox)Wap-Cre) fail to accumulate lobuloalveoli or successfully engage lactation at parturition owing, in part, to impaired epithelial proliferation [8].
  • By use of newly developed subcongenic strains of mice from a parental B6.129-Il10-/- knockout/congenic strain, we have narrowed the critical region for a new behavioral QTL, called Emo4, for open-field activity to a segment of Chromosome 1 between Erbb4 (68.4Mb) and B3gnt7 (86.2 Mb) [9].
  • In addition, constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts [10].
  • Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia [11].
  • ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4 [12].

Anatomical context of Erbb4


Associations of Erbb4 with chemical compounds

  • In contrast, no tumors grew in mice injected with 32D/EGFR, 32D/ErbB-4, and 32D/ErbB-2+ErbB-3 cells or low-expressing clone 32D/EGFRvIII C2 cells or the parental 32D cells [17].
  • Immunologic analysis demonstrates that TPA treatment of cells induces the proteolytic cleavage of ErbB-4, producing an 80-kDa cytoplasmic domain fragment, which contains a low level of phosphotyrosine, and a 120-kDa ectodomain fragment, which is released into the extracellular medium [18].
  • A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis [19].
  • Cleavage of ErbB-4 was also enhanced by other protein kinase C activators, i.e. platelet-derived growth factor, ionomycin, and synthetic diacylglycerol, while protein kinase C inhibition or down-regulation suppressed the TPA stimulation of ErbB-4 degradation [18].
  • A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester [20].
  • We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway [21].

Physical interactions of Erbb4

  • Furthermore, the neural tube activity is blocked by a hybrid protein containing the NDF-binding domain of the ErbB4 receptor, strongly implicating NDF in the physiological transition [22].

Regulatory relationships of Erbb4


Other interactions of Erbb4

  • Localized expression of Nrg3 and its receptor, Erbb4, in the presumptive mammary region around the future bud site prior to morphological appearance of buds and the expression of bud epithelial markers further support an inductive role [26].
  • Expression of ErbB3, ErbB4, and neuregulin-1 mRNA during tooth development [27].
  • We speculate that the therapeutic effect of WTACE2 could have been due to effects on several TACE targets, including TGF-alpha, AR, and ErbB4, as well as metalloproteinases other than TACE [28].
  • Layer and age specific regulation was observed for the ErbB4 splice variants JMa/JMb and NRG-1-beta1/beta2 forms [29].
  • At the molecular level, reduced expression of epidermal growth factor receptor, attenuated protein cleavage of ErbB4, and changes in MAPK activation were also detected in TACE(DeltaZn/DeltaZn) knockout heart tissues [30].
  • We found that full prolactin-mediated STAT5A activation and binding to the endogenous beta-casein promoter required ErbB4/HER4 but did not require ErbB1/epidermal growth factor receptor [31].

Analytical, diagnostic and therapeutic context of Erbb4


  1. Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Ferretti, E., Di Marcotullio, L., Gessi, M., Mattei, T., Greco, A., Po, A., De Smaele, E., Giangaspero, F., Riccardi, R., Di Rocco, C., Pazzaglia, S., Maroder, M., Alimandi, M., Screpanti, I., Gulino, A. Oncogene (2006) [Pubmed]
  2. Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo. Tang, C.K., Concepcion, X.Z., Milan, M., Gong, X., Montgomery, E., Lippman, M.E. Cancer Res. (1999) [Pubmed]
  3. Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Pinkas-Kramarski, R., Eilam, R., Alroy, I., Levkowitz, G., Lonai, P., Yarden, Y. Oncogene (1997) [Pubmed]
  4. Closed head injury induces up-regulation of ErbB-4 receptor at the site of injury. Erlich, S., Shohami, E., Pinkas-Kramarski, R. Mol. Cell. Neurosci. (2000) [Pubmed]
  5. Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Junttila, T.T., Laato, M., Vahlberg, T., Söderström, K.O., Visakorpi, T., Isola, J., Elenius, K. Clin. Cancer Res. (2003) [Pubmed]
  6. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Gassmann, M., Casagranda, F., Orioli, D., Simon, H., Lai, C., Klein, R., Lemke, G. Nature (1995) [Pubmed]
  7. gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Ni, C.Y., Murphy, M.P., Golde, T.E., Carpenter, G. Science (2001) [Pubmed]
  8. Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Long, W., Wagner, K.U., Lloyd, K.C., Binart, N., Shillingford, J.M., Hennighausen, L., Jones, F.E. Development (2003) [Pubmed]
  9. Two new behavioral QTLs, Emo4 and Reb1, map to mouse Chromosome 1: Congenic strains and candidate gene identification studies. de Ledesma, A.M., Desai, A.N., Bolivar, V.J., Symula, D.J., Flaherty, L. Mamm. Genome (2006) [Pubmed]
  10. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Iwamoto, R., Yamazaki, S., Asakura, M., Takashima, S., Hasuwa, H., Miyado, K., Adachi, S., Kitakaze, M., Hashimoto, K., Raab, G., Nanba, D., Higashiyama, S., Hori, M., Klagsbrun, M., Mekada, E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Neuregulin 1 and susceptibility to schizophrenia. Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., Brynjolfsson, J., Gunnarsdottir, S., Ivarsson, O., Chou, T.T., Hjaltason, O., Birgisdottir, B., Jonsson, H., Gudnadottir, V.G., Gudmundsdottir, E., Bjornsson, A., Ingvarsson, B., Ingason, A., Sigfusson, S., Hardardottir, H., Harvey, R.P., Lai, D., Zhou, M., Brunner, D., Mutel, V., Gonzalo, A., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. Am. J. Hum. Genet. (2002) [Pubmed]
  12. ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4. Wang, L.M., Kuo, A., Alimandi, M., Veri, M.C., Lee, C.C., Kapoor, V., Ellmore, N., Chen, X.H., Pierce, J.H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  13. Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Zhang, D., Sliwkowski, M.X., Mark, M., Frantz, G., Akita, R., Sun, Y., Hillan, K., Crowley, C., Brush, J., Godowski, P.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: a possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. Paria, B.C., Elenius, K., Klagsbrun, M., Dey, S.K. Development (1999) [Pubmed]
  15. Targeted inhibition of tumor-cell growth by recombinant heregulin-toxin fusion proteins. Jeschke, M., Wels, W., Dengler, W., Imber, R., Stöcklin, E., Groner, B. Int. J. Cancer (1995) [Pubmed]
  16. Developmental profile of ErbB receptors in murine central nervous system: implications for functional interactions. Fox, I.J., Kornblum, H.I. J. Neurosci. Res. (2005) [Pubmed]
  17. Epidermal growth factor receptor vIII enhances tumorigenicity in human breast cancer. Tang, C.K., Gong, X.Q., Moscatello, D.K., Wong, A.J., Lippman, M.E. Cancer Res. (2000) [Pubmed]
  18. Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation. Vecchi, M., Baulida, J., Carpenter, G. J. Biol. Chem. (1996) [Pubmed]
  19. A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis. Kainulainen, V., Sundvall, M., Määttä, J.A., Santiestevan, E., Klagsbrun, M., Elenius, K. J. Biol. Chem. (2000) [Pubmed]
  20. A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. Elenius, K., Corfas, G., Paul, S., Choi, C.J., Rio, C., Plowman, G.D., Klagsbrun, M. J. Biol. Chem. (1997) [Pubmed]
  21. ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. Krivosheya, D., Tapia, L., Levinson, J.N., Huang, K., Kang, Y., Hines, R., Ting, A.K., Craig, A.M., Mei, L., Bamji, S.X., El-Husseini, A. J. Biol. Chem. (2008) [Pubmed]
  22. The regulation of Krox-20 expression reveals important steps in the control of peripheral glial cell development. Murphy, P., Topilko, P., Schneider-Maunoury, S., Seitanidou, T., Baron-Van Evercooren, A., Charnay, P. Development (1996) [Pubmed]
  23. Topical epiregulin enhances repair of murine excisional wounds. Draper, B.K., Komurasaki, T., Davidson, M.K., Nanney, L.B. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. (2003) [Pubmed]
  24. ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation. Jones, F.E., Welte, T., Fu, X.Y., Stern, D.F. J. Cell Biol. (1999) [Pubmed]
  25. Regulation of functional nitric oxide synthase-1 expression in cerebellar granule neurons by heregulin is post-transcriptional, and involves mitogen-activated protein kinase. Krainock, R., Murphy, S. J. Neurochem. (2001) [Pubmed]
  26. Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Howard, B., Panchal, H., McCarthy, A., Ashworth, A. Genes Dev. (2005) [Pubmed]
  27. Expression of ErbB3, ErbB4, and neuregulin-1 mRNA during tooth development. Fried, K., Risling, M., Tidcombe, H., Gassmann, M., Lillesaar, C. Dev. Dyn. (2002) [Pubmed]
  28. Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease. Nemo, R., Murcia, N., Dell, K.M. Pediatr. Res. (2005) [Pubmed]
  29. Differential expression of neuregulins and their receptors in the olfactory bulb layers of the developing mouse. Bovetti, S., De Marchis, S., Gambarotta, G., Fasolo, A., Perroteau, I., Puche, A.C., Bovolin, P. Brain Res. (2006) [Pubmed]
  30. TACE is required for fetal murine cardiac development and modeling. Shi, W., Chen, H., Sun, J., Buckley, S., Zhao, J., Anderson, K.D., Williams, R.G., Warburton, D. Dev. Biol. (2003) [Pubmed]
  31. Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation. Muraoka-Cook, R.S., Sandahl, M., Hunter, D., Miraglia, L., Earp, H.S. Mol. Endocrinol. (2008) [Pubmed]
  32. Laminin-1 and epidermal growth factor family members co-stimulate fetal pancreas cell proliferation and colony formation. Jiang, F.X., Harrison, L.C. Differentiation (2005) [Pubmed]
  33. erbB genes in the mouse uterus: cell-specific signaling by epidermal growth factor (EGF) family of growth factors during implantation. Lim, H., Das, S.K., Dey, S.K. Dev. Biol. (1998) [Pubmed]
  34. The involvement of ErbB4 with schizophrenia: association and expression studies. Silberberg, G., Darvasi, A., Pinkas-Kramarski, R., Navon, R. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2006) [Pubmed]
  35. Exogenous interferon-gamma alters murine inner cell mass and trophoblast development. Effect on the expression of ErbB1, ErbB4 and heparan sulfate proteoglycan (perlecan). Fontana, V., Choren, V., Vauthay, L., Calvo, J.C., Calvo, L., Cameo, M. Reproduction (2004) [Pubmed]
WikiGenes - Universities