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

• Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart [9].
• In this issue of Cell, work by López-Bendito et al.(2006) reveals that tangentially migrating cells within the ventral telencephalon are essential for axonal navigation between the thalamus and the neocortex, a process apparently mediated by Neuregulin-1/ErbB4 short- and long-range signaling [10].
• We found that NRG1 stimulation suppresses NMDA receptor activation in the human prefrontal cortex, as previously reported in the rodent cortex [11].
• Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia [11].
• Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia [11].

Chemical compound and disease context of NRG1

• Soluble TR stimulated erbB-4 tyrosine phosphorylation in MKN 28 gastric cancer cells, although it was weak compared to neuregulin-induced erbB-4 tyrosine phosphorylation; this suggests that TR might be a ligand for erbB-4- or erbB-4-related receptor tyrosine kinase [12].
• Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer [13].
• Profiling of other estrogen receptor-positive breast cancer cell lines, MCF7 and SUM44, yielded a group of twenty-one genes whose transcripts are upregulated by NRG in all three lines tested [14].
• Recent studies have suggested that autocrine production of Neuregulin (NRG), a growth factor that activates members of the Epidermal Growth Factor Receptor/ErbB family of proto-oncogenes, is sufficient for breast tumor initiation and progression [14].
• To investigate the role of prostaglandin (PG) E1 in preventing scar formation as well as that of the related cytokines, we culture fibroblasts from hypertrophic scar tissue (SDF) and normal dermis (NDF) collected from patients with scar contracture [15].

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

• Therefore, these findings suggest that enhanced NRG1 signaling may contribute to NMDA hypofunction in schizophrenia [11].
• We treated the cells with the ErbB4 ligands betacellulin (BTC) and neuregulin1beta (NRG1 beta) and assayed ErbB4 tyrosine phosphorylation [24].
• METHODS: In the present study, we examined the effect of NRG on LNCaP cell growth and survival in the absence of androgen mimetic by the MTT assay, FACS analysis, nuclei staining, and Western blotting [25].
• However, NRG-induced cell death was inhibited by type II cell death inhibitor, 3-methyladenine [25].
• Neuregulin is a factor essential for synapse-specific transcription of acetylcholine receptor genes at the neuromuscular junction [26].

Physical interactions of NRG1

• Consistent with specificity to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor [27].
• Previous biophysical studies suggest that the ErbB3 extracellular region remains monomeric when bound to NRG [28].
• According to this model, EGF binding to NDF-occupied heterodimers is partially blocked [29].
• NRG-1 induces cell proliferation through a high-affinity receptor complex composed of a heterodimer of human epidermal growth factor-like receptor (HER) 2 and 3 [30].
• This paper presents evidence that NRG receptors--ErbB receptor tyrosine kinases interact with distinct PDZ domain-containing proteins that are localized at the neuromuscular junction (NMJ) [31].

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

• ADAM19 colocalized with tubular and interstitial NRG, however, not with HB-EGF [23].

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

• Levels of NRG1 and erbB4, however, did not differ between schizophrenia and control groups [11].
• Furthermore, conditioned medium from VS cell cultures contains NRG1 and stimulates SC proliferation in SC cultures, an effect that is inhibited by anti-NRG1 and HCN [38].
• PCR analysis of reverse-transcribed cell line RNAs revealed an extensive complexity of the NRG1 transcripts but failed to detect a consistent pattern of mRNA isoforms in the cell lines with NRG1 breakpoint [3].
• Immunofluorescence microscopy showed that the two ErbB receptors as well as ErbB1 were expressed mainly in the epithelium, whereas NRG-1 was exclusively found in the mesenchyme [39].
• The NRG1-alpha isoforms' expression was studied in 115 locally advanced adenocarcinomas of the breast using immunohistochemistry [40].

References