{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuregulin‐2 (NRG2) is a member of the neuregulin family of epidermal growth factor–like ligands that interact with ErbB receptor tyrosine kinases. Several studies have demonstrated that NRG2, also known as NTAK, can directly bind to ErbB3 and ErbB4 and transactivate ErbB2, thereby influencing diverse signaling pathways. Notably, NRG2 exists as multiple isoforms whose alternative splicing determines their tissue‐specific activities. For instance, one study showed that specific NRG2 isoforms are critical in modulating angiogenic responses in endothelial cells, whereas other isoforms regulate synapse‐specific acetylcholine receptor transcription at the neuromuscular junction. This heterogeneity is further highlighted by isoform‐specific differences, as the NRG2β variant exhibits potent stimulation of ErbB4 phosphorylation and coupling—properties that depend on key residues within its EGF‐like domain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of oncogenesis, emerging evidence suggests that NRG2 plays a multifaceted role. The identification of NRG2 fusions in solid tumors points to a mechanism whereby the neuregulin ligand is mislocalized in proximity to ErbB receptors, triggering aberrant receptor activation and downstream proliferative signaling. Moreover, studies employing NRG2β mutants that function as partial agonists have demonstrated the capacity to stimulate receptor phosphorylation without inducing cell proliferation—a finding that provides a basis for novel therapeutic strategies against ErbB4‐dependent melanomas. In gliomas, investigations of NRG2 expression have raised the possibility that deregulated NRG2 signaling may contribute to tumor development and progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in receptor signaling and tumor biology, NRG2 has also been implicated in cellular stress responses and neurodevelopment. One study identified NRG2 as a novel component of stress granules, demonstrating that its depletion markedly inhibits stress granule formation and can modulate cell survival under adverse conditions. In parallel, alterations in NRG2 expression have been linked to clinical phenotypes in neurodevelopmental and ocular disorders. For example, reduced NRG2 expression has been observed in autism spectrum disorder, suggesting that NRG2 may be a susceptibility gene for neurodevelopmental impairment, while its positional candidacy in a glaucoma locus points to a potential role in juvenile-onset primary open-angle glaucoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Norihiko Nakano, Shigeki Higashiyama, Hiroshi Ohmoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The N-terminal region of NTAK/neuregulin-2 isoforms has an inhibitory activity on angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M311045200"}], "href": "https://doi.org/10.1074/jbc.M311045200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14722120"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14722120"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "O N Ponomareva, H Ma, R Dakour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stimulation of acetylcholine receptor transcription by neuregulin-2 requires an N-box response element and is regulated by alternative splicing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroscience (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuroscience.2005.04.028"}], "href": "https://doi.org/10.1016/j.neuroscience.2005.04.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15961242"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15961242"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kristy J Wilson, Christopher P Mill, Elizabeth M Cameron, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inter-conversion of neuregulin2 full and partial agonists for ErbB4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2007.10.004"}], "href": "https://doi.org/10.1016/j.bbrc.2007.10.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17945187"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17945187"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Richard L Cullum, Lauren M Lucas, Jared I Senfeld, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0243901"}], "href": "https://doi.org/10.1371/journal.pone.0243901"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33378376"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33378376"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei-Jiang Zhao, San-Jun Yi, Guan-Yong Ou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuregulin 2 (NRG2) is expressed in gliomas and promotes migration of human glioma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Folia Neuropathol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5114/fn.2021.106460"}], "href": "https://doi.org/10.5114/fn.2021.106460"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34284546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34284546"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "W Zhao, J Lin "}, {"type": "b", "children": [{"type": "t", "text": "[Neuregulin 2 is highly expressed in glioma tissues to regulate glial fibrillary acidic protein expression "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "via"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Akt signaling]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nan Fang Yi Ke Da Xue Xue Bao (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.12122/j.issn.1673-4254.2021.08.07"}], "href": "https://doi.org/10.12122/j.issn.1673-4254.2021.08.07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34549707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34549707"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Misako Nagasaka, Sai-Hong Ignatius Ou "}, {"type": "b", "children": [{"type": "t", "text": "NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Cancer (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.trecan.2021.11.003"}], "href": "https://doi.org/10.1016/j.trecan.2021.11.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34996744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34996744"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Bao Jian Fan, Wendy Charles Ko, Dan Yi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fine mapping of new glaucoma locus GLC1M and exclusion of neuregulin 2 as the causative gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17563728"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17563728"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jin Ah Kim, Aravinth Kumar Jayabalan, Vinoth Kumar Kothandan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of Neuregulin-2 as a novel stress granule component."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMB Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5483/bmbrep.2016.49.8.090"}], "href": "https://doi.org/10.5483/bmbrep.2016.49.8.090"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27345716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27345716"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Wei-Hsien Chien, Chia-Hsiang Chen, Min-Chih Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuregulin 2 Is a Candidate Gene for Autism Spectrum Disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms25105547"}], "href": "https://doi.org/10.3390/ijms25105547"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38791584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38791584"}]}]}]}