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Gene Review

NRG2  -  neuregulin 2

Homo sapiens

Synonyms: DON1, Don-1, HRG2, NTAK, Pro-NRG2, ...
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Disease relevance of NRG2

  • These observations suggest that autocrine, paracrine, and/or juxtacrine NRG-1/NRG-2 signaling promotes schwannoma pathogenesis and that this signaling pathway may be an important therapeutic target in schwannomas [1].
  • 0kb long mRNA of the human NTAK gene was expressed in the human neuroblastoma SK-N-SH cell line with two alternative isoforms detected [2].

High impact information on NRG2

  • Two of the neuregulins (NRG1 and NRG2) and their receptors (erbB2 and erbB4) are essential for normal cardiac development and can mediate hypertrophic growth and enhance survival of embryonic, postnatal, and adult rat ventricular myocytes [3].
  • Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus [4].
  • In contrast to those of neuregulin, high levels of expression of Don-1 are restricted to the cerebellum and dentate gyrus in the adult brain and to fetal tissues [4].
  • These results suggest that the active site of NTAK is localized outside of the EGF-like domain but within the N-terminal region, including the Ig-like domain, of NTAK [5].
  • Because ErbB signaling has been implicated in various angiogenic mechanisms, the effect of NTAK (which has at least nine isoforms due to alternative splicing) in angiogenesis is explored [5].

Biological context of NRG2

  • Preincubation of MCF-7 cells with PG-J(2) before addition of NRG1 and NRG2 had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle, and a marked increase in apoptosis [6].
  • In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns [7].
  • 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 [8].
  • We have isolated and characterized the human NTAK gene, comprising 12 exons spanning in excess of 55 kilobases (kb) [2].
  • Stimulation of acetylcholine receptor transcription by neuregulin-2 requires an N-box response element and is regulated by alternative splicing [9].

Anatomical context of NRG2

  • In cerebellum, NRG-2 colocalizes with calbindin in proximal dendrites and soma of Purkinje cells [10].
  • Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells [11].
  • Neoplastic Schwann cells almost uniformly express erbB2 and erbB3, 2 membrane receptor tyrosine kinases mediating NRG-1 and NRG-2 action [1].
  • In vivo, NTAK is only expressed in the brain of rat E11.5 embryos, and in the brain and thymus of adult rats [12].
  • They also raise the possibility that Schwann cell-derived Nrg-2 could activate ErbB receptors on the synaptic sarcolemma and that this could account, at least in part, for the Nrg-mediated regulation of AChR expression [13].

Physical interactions of NRG2

  • Although neuregulin-1 and neuregulin-2 are both binding ligands for the ErbB3 and ErbB4 receptors, they exhibit distinct biological activities depending on cellular context [14].

Other interactions of NRG2

  • Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells [6].
  • However, the biological relevance of NRG2 and NRG3 remains elusive [15].


  1. 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]
  2. Characterization of the human NTAK gene structure and distribution of the isoforms for rat NTAK mRNA. Yamada, K., Ichino, N., Nishii, K., Sawada, H., Higashiyama, S., Ishiguro, H., Nagatsu, T. Gene (2000) [Pubmed]
  3. Neuregulin signaling in the heart. Dynamic targeting of erbB4 to caveolar microdomains in cardiac myocytes. Zhao, Y.Y., Feron, O., Dessy, C., Han, X., Marchionni, M.A., Kelly, R.A. Circ. Res. (1999) [Pubmed]
  4. Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Busfield, S.J., Michnick, D.A., Chickering, T.W., Revett, T.L., Ma, J., Woolf, E.A., Comrack, C.A., Dussault, B.J., Woolf, J., Goodearl, A.D., Gearing, D.P. Mol. Cell. Biol. (1997) [Pubmed]
  5. The N-terminal region of NTAK/neuregulin-2 isoforms has an inhibitory activity on angiogenesis. Nakano, N., Higashiyama, S., Ohmoto, H., Ishiguro, H., Taniguchi, N., Wada, Y. J. Biol. Chem. (2004) [Pubmed]
  6. 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]
  7. The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q. Ring, H.Z., Chang, H., Guilbot, A., Brice, A., LeGuern, E., Francke, U. Hum. Genet. (1999) [Pubmed]
  8. 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]
  9. Stimulation of acetylcholine receptor transcription by neuregulin-2 requires an N-box response element and is regulated by alternative splicing. Ponomareva, O.N., Ma, H., Dakour, R., Raabe, T.D., Lai, C., Rimer, M. Neuroscience (2005) [Pubmed]
  10. Neuregulin-2 is developmentally regulated and targeted to dendrites of central neurons. Longart, M., Liu, Y., Karavanova, I., Buonanno, A. J. Comp. Neurol. (2004) [Pubmed]
  11. Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Mahtouk, K., Cremer, F.W., R??me, T., Jourdan, M., Baudard, M., Moreaux, J., Requirand, G., Fiol, G., De Vos, J., Moos, M., Quittet, P., Goldschmidt, H., Rossi, J.F., Hose, D., Klein, B. Oncogene (2006) [Pubmed]
  12. A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4. Higashiyama, S., Horikawa, M., Yamada, K., Ichino, N., Nakano, N., Nakagawa, T., Miyagawa, J., Matsushita, N., Nagatsu, T., Taniguchi, N., Ishiguro, H. J. Biochem. (1997) [Pubmed]
  13. Schwann cell-derived neuregulin-2alpha can function as a cell-attached activator of muscle acetylcholine receptor expression. Ponomareva, O.N., Fischer, T.M., Lai, C., Rimer, M. Glia (2006) [Pubmed]
  14. Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2. Crovello, C.S., Lai, C., Cantley, L.C., Carraway, K.L. J. Biol. Chem. (1998) [Pubmed]
  15. 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]
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