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Gene Review

NRG1  -  neuregulin 1

Homo sapiens

Synonyms: ARIA, GGF, GGF2, HGL, HRG, ...
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Disease relevance of NRG1

  • We have now screened for breaks at NRG1 in paraffin sections of breast tumors [1].
  • Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers [1].
  • Furthermore, the expression of all three components of the proposed autocrine loop (ie., ErbB-2, ErbB-4, and NRG1-beta) was significantly related to the presence of metastases at diagnosis (P < 0.05) [2].
  • We also demonstrate NRG1-beta expression in 87% (n = 46 of 48) of medulloblastoma primary tumors, with the greatest expression levels occurring in tumors with high ErbB-2 and ErbB-4 receptor coexpression [2].
  • This suggests that the NRG1 locus is a recurring target of translocations in carcinomas [3].

Psychiatry related information on NRG1

  • Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited [4].
  • Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1 [5].
  • To replicate this finding and assess the association between age at onset of schizophrenia and the NRG1 Arg38Gln polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (228 schizophrenic disorder patients and 269 controls) [6].
  • A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes [7].
  • Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses [8].

High impact information on NRG1


Chemical compound and disease context of NRG1


Biological context of NRG1

  • This direct replication of haplotype association in a second population further implicates NRG1 as a factor that contributes to the etiology of schizophrenia [16].
  • The NRG1/neuregulins are a diverse family of proteins that arise by alternative splicing from a single gene [17].
  • Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection [18].
  • The recently isolated second family of neuregulins, NRG2, shares its primary receptors, ErbB-3 and ErbB-4, and induction of mammary cell differentiation with NRG1 isoforms, suggesting functional redundancy of the two growth factor families [19].
  • A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene [1].

Anatomical context of NRG1

  • We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression [1].
  • Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039) [20].
  • At the cellular level, NRG1 mRNA was abundant in hippocampal and cortical pyramidal neurons and some interneurons, and in cerebellar Purkinje cells and Golgi cells [21].
  • We report that neoplastic Schwann cells within schwannomas overexpress multiple alpha and beta transmembrane precursors from the class II and class III NRG-1 subfamilies [22].
  • It can cleave epidermal growth factor (EGF)-like growth factors, such as heparin-binding (HB)-EGF and neuregulin (NRG), from the cell membrane [23].

Associations of NRG1 with chemical compounds


Physical interactions of NRG1


Enzymatic interactions of NRG1

  • In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-kappa B site deleted and mutated form were significantly reduced after HRG-beta 1 treatment as compared with the 1.5-kb VEGF-C promoter [32].

Co-localisations of NRG1


Regulatory relationships of NRG1

  • RESULTS: Our results demonstrate that NRG activates ErbB-2/ErbB-3 heterodimers and induces cell death of LNCaP cells [25].
  • In this study, we identified that HRG-beta 1 stimulated up-regulation of VEGF-C mRNA and protein of human breast cancer cells in a dosage- and time-dependent manner and that this up-regulation was de novo RNA synthesis-dependent [32].
  • Interestingly, the HRG-beta 1-induced NF-kappa B activation cascade was also effectively blocked by SB203580 treatment or p38AF transfection [32].
  • Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation [30].
  • Here we show that NDF inhibits EGF binding in a cell type-specific manner [29].
  • PKA directly phosphorylated ErbB2 on Thr-686, a highly conserved intracellular regulatory site that was required for the PKA-mediated synergistic enhancement of neuregulin-induced ErbB2-ErbB3 activation and proliferation in SCs [33].

Other interactions of NRG1

  • This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro [34].
  • Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells [35].
  • Neuregulins 1, 2 and 3 (NRG1, NRG2 and NRG3) are expressed in the mammalian nervous system [36].
  • The c-erbB-4 receptor and all of the ligands examined, neuregulin alpha, neuregulin beta, and betacellulin, were expressed at significantly higher levels in the secretory as compared with the proliferative phase of the menstrual cycle, suggesting a role for these proteins in endometrial maturation [37].
  • NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2 [1].

Analytical, diagnostic and therapeutic context of NRG1


  1. A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene. Huang, H.E., Chin, S.F., Ginestier, C., Bardou, V.J., Adélaïde, J., Iyer, N.G., Garcia, M.J., Pole, J.C., Callagy, G.M., Hewitt, S.M., Gullick, W.J., Jacquemier, J., Caldas, C., Chaffanet, M., Birnbaum, D., Edwards, P.A. Cancer Res. (2004) [Pubmed]
  2. Expression of the ErbB-neuregulin signaling network during human cerebellar development: implications for the biology of medulloblastoma. Gilbertson, R.J., Clifford, S.C., MacMeekin, W., Meekin, W., Wright, C., Perry, R.H., Kelly, P., Pearson, A.D., Lunec, J. Cancer Res. (1998) [Pubmed]
  3. A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. Adélaïde, J., Huang, H.E., Murati, A., Alsop, A.E., Orsetti, B., Mozziconacci, M.J., Popovici, C., Ginestier, C., Letessier, A., Basset, C., Courtay-Cahen, C., Jacquemier, J., Theillet, C., Birnbaum, D., Edwards, P.A., Chaffanet, M. Genes Chromosomes Cancer (2003) [Pubmed]
  4. Genetics of schizophrenia and affective disorders. Maier, W., Zobel, A., Rietschel, M. Pharmacopsychiatry (2003) [Pubmed]
  5. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. Craddock, N., O'Donovan, M.C., Owen, M.J. J. Med. Genet. (2005) [Pubmed]
  6. Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia. Hong, C.J., Huo, S.J., Liao, D.L., Lee, K., Wu, J.Y., Tsai, S.J. Neurosci. Lett. (2004) [Pubmed]
  7. Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population. Kim, J.W., Lee, Y.S., Cho, E.Y., Jang, Y.L., Park, D.Y., Choi, K.S., Jeun, H.O., Cho, S.H., Jang, S.Y., Hong, K.S. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2006) [Pubmed]
  8. Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses. Go, R.C., Perry, R.T., Wiener, H., Bassett, S.S., Blacker, D., Devlin, B., Sweet, R.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  9. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Brutsaert, D.L. Physiol. Rev. (2003) [Pubmed]
  10. Building bridges to the cortex. Hanashima, C., Molnár, Z., Fishell, G. Cell (2006) [Pubmed]
  11. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Hahn, C.G., Wang, H.Y., Cho, D.S., Talbot, K., Gur, R.E., Berrettini, W.H., Bakshi, K., Kamins, J., Borgmann-Winter, K.E., Siegel, S.J., Gallop, R.J., Arnold, S.E. Nat. Med. (2006) [Pubmed]
  12. A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells. Uchida, T., Wada, K., Akamatsu, T., Yonezawa, M., Noguchi, H., Mizoguchi, A., Kasuga, M., Sakamoto, C. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  13. Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. Bacus, S.S., Gudkov, A.V., Zelnick, C.R., Chin, D., Stern, R., Stancovski, I., Peles, E., Ben-Baruch, N., Farbstein, H., Lupu, R. Cancer Res. (1993) [Pubmed]
  14. Neuregulin-regulated gene expression in mammary carcinoma cells. Amin, D.N., Tuck, D., Stern, D.F. Exp. Cell Res. (2005) [Pubmed]
  15. Effects of prostaglandin E1 on cultured dermal fibroblasts from normal and hypertrophic scarred skin. Zhou, L.J., Inoue, M., Gunji, H., Ono, I., Kaneko, F. J. Dermatol. Sci. (1997) [Pubmed]
  16. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Stefansson, H., Sarginson, J., Kong, A., Yates, P., Steinthorsdottir, V., Gudfinnsson, E., Gunnarsdottir, S., Walker, N., Petursson, H., Crombie, C., Ingason, A., Gulcher, J.R., Stefansson, K., St Clair, D. Am. J. Hum. Genet. (2003) [Pubmed]
  17. 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]
  18. Recent advances in the genetics of schizophrenia. O'Donovan, M.C., Williams, N.M., Owen, M.J. Hum. Mol. Genet. (2003) [Pubmed]
  19. ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network. Pinkas-Kramarski, R., Shelly, M., Guarino, B.C., Wang, L.M., Lyass, L., Alroy, I., Alimandi, M., Kuo, A., Moyer, J.D., Lavi, S., Eisenstein, M., Ratzkin, B.J., Seger, R., Bacus, S.S., Pierce, J.H., Andrews, G.C., Yarden, Y., Alamandi, M. Mol. Cell. Biol. (1998) [Pubmed]
  20. Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Petryshen, T.L., Middleton, F.A., Kirby, A., Aldinger, K.A., Purcell, S., Tahl, A.R., Morley, C.P., McGann, L., Gentile, K.L., Rockwell, G.N., Medeiros, H.M., Carvalho, C., Macedo, A., Dourado, A., Valente, J., Ferreira, C.P., Patterson, N.J., Azevedo, M.H., Daly, M.J., Pato, C.N., Pato, M.T., Sklar, P. Mol. Psychiatry (2005) [Pubmed]
  21. Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Law, A.J., Shannon Weickert, C., Hyde, T.M., Kleinman, J.E., Harrison, P.J. Neuroscience (2004) [Pubmed]
  22. Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. Stonecypher, M.S., Chaudhury, A.R., Byer, S.J., Carroll, S.L. J. Neuropathol. Exp. Neurol. (2006) [Pubmed]
  23. ADAM19 expression in human nephrogenesis and renal disease: Associations with clinical and structural deterioration. Melenhorst, W.B., van den Heuvel, M.C., Timmer, A., Huitema, S., Bulthuis, M., Timens, W., van Goor, H. Kidney Int. (2006) [Pubmed]
  24. ErbB2 and ErbB3 do not quantitatively modulate ligand-induced ErbB4 tyrosine phosphorylation. Feroz, K., Williams, E., Riese, D.J. Cell. Signal. (2002) [Pubmed]
  25. Neuregulin promotes autophagic cell death of prostate cancer cells. Tal-Or, P., Di-Segni, A., Lupowitz, Z., Pinkas-Kramarski, R. Prostate (2003) [Pubmed]
  26. Erbin is a protein concentrated at postsynaptic membranes that interacts with PSD-95. Huang, Y.Z., Wang, Q., Xiong, W.C., Mei, L. J. Biol. Chem. (2001) [Pubmed]
  27. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Harari, D., Tzahar, E., Romano, J., Shelly, M., Pierce, J.H., Andrews, G.C., Yarden, Y. Oncogene (1999) [Pubmed]
  28. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. Berger, M.B., Mendrola, J.M., Lemmon, M.A. FEBS Lett. (2004) [Pubmed]
  29. Neu differentiation factor inhibits EGF binding. A model for trans-regulation within the ErbB family of receptor tyrosine kinases. Karunagaran, D., Tzahar, E., Liu, N., Wen, D., Yarden, Y. J. Biol. Chem. (1995) [Pubmed]
  30. Neuregulin-1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Liu, J., Kern, J.A. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
  31. Compartmentalized NRG signaling and PDZ domain-containing proteins in synapse structure and function. Huang, Y.Z., Wang, Q., Won, S., Luo, Z.G., Xiong, W.C., Mei, L. Int. J. Dev. Neurosci. (2002) [Pubmed]
  32. Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway. Tsai, P.W., Shiah, S.G., Lin, M.T., Wu, C.W., Kuo, M.L. J. Biol. Chem. (2003) [Pubmed]
  33. Protein kinase A-mediated gating of neuregulin-dependent ErbB2-ErbB3 activation underlies the synergistic action of cAMP on Schwann cell proliferation. Monje, P.V., Athauda, G., Wood, P.M. J. Biol. Chem. (2008) [Pubmed]
  34. The N-terminal Domains of Neuregulin 1 Confer Signal Attenuation. Warren, C.M., Kani, K., Landgraf, R. J. Biol. Chem. (2006) [Pubmed]
  35. The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells. Pignatelli, M., Cortés-Canteli, M., Lai, C., Santos, A., Perez-Castillo, A. J. Cell. Sci. (2001) [Pubmed]
  36. Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival. Carteron, C., Ferrer-Montiel, A., Cabedo, H. J. Cell. Sci. (2006) [Pubmed]
  37. Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Srinivasan, R., Benton, E., McCormick, F., Thomas, H., Gullick, W.J. Clin. Cancer Res. (1999) [Pubmed]
  38. Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation. Hansen, M.R., Roehm, P.C., Chatterjee, P., Green, S.H. Glia (2006) [Pubmed]
  39. Tissue interaction mediated by neuregulin-1 and ErbB receptors regulates epithelial morphogenesis of mouse embryonic submandibular gland. Miyazaki, Y., Nakanishi, Y., Hieda, Y. Dev. Dyn. (2004) [Pubmed]
  40. Neuregulin 1-alpha expression in locally advanced breast cancer. Raj, E.H., Skinner, A., Mahji, U., Nirmala, K.N., Ravichandran, K., Shanta, V., Hurst, H.C., Gullick, W.J., Rajkumar, T. Breast (Edinburgh, Scotland) (2001) [Pubmed]
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