Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4

Zhang, Dongxiao; Sliwkowski, Mark X.; Mark, Melanie R.; Frantz, Gretchen; Akita, Robert W.; Sun, Yang; Hillan, Kenneth J.; Crowley, Craig; Brush, Jennifer; Godowski, Paul J.

doi:10.1073/pnas.94.18.9562

Cited by 357 publications

(292 citation statements)

References 44 publications

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“…The EGF-like domain of NRG-4 exhibits restricted binding specificity, it directly binds to ErbB-4, but not to ErbB-1, ErbB-2 or ErbB-3. A similar selective binding to ErbB-4 has also been reported for NRG-3 (Zhang et al, 1997) and may indicate that during development and in the adult, ligands with restricted ErbB speci®cities may play important roles. It is interesting to note that NRG-3 is the EGF-like ligand closest to NRG-4 (42% sequence identity in the EGF-like domain).…”

Section: Discussionsupporting

confidence: 68%

“…Besides speci®city to ErbB-4, NRG-3 and NRG-4 share relatively low a nity to this receptor compared with NRG-1 (Figure 4 and Zhang et al, 1997). Several other ligands, such as epiregulin and the alpha isoform of NRG-1 (Tzahar et al, 1994), also display relatively low a nity to ErbB-4.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple isoforms of NRG-1 exist which amongst other roles, permit heterogeneous binding a nities to di erent ErbB complexes (Tzahar et al, 1994). The NRG family now includes also two isoforms of NRG-2 (Bus®eld et al, 1997;Carraway et al, 1997;Chang et al, 1997;Higashiyama et al, 1997), of which the alpha isoform is a pan-ErbB ligand , and NRG-3, a ligand of ErbB-4 (Zhang et al, 1997). The multiplicity of genes encoding ErbB-1 ligands, contrasting with the small number of known genes encoding ligands for ErbB-3 or ErbB-4 (namely: NRGs), led us to believe in the existence of additional NRG genes in the genome of mammals.…”

Section: Introductionmentioning

confidence: 99%

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Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

et al. 1999

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The ErbB/HER family of receptor tyrosine kinases consists of four receptors that bind a large number of growth factor ligands sharing an epidermal growth factor-(EGF)-like motif. Whereas ErbB-1 binds seven di erent ligands whose prototype is EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain. A synthetic peptide encompassing the full-length EGF-like domain can induce growth of interleukin-dependent cells ectopically expressing ErbB-4, but not cells expressing the other three ErbB proteins or their combinations. Consistent with speci®city to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor. Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA. The primary structure and the pattern of expression of NRG-4, together with the strict speci®city of this growth factor to ErbB-4, suggest a physiological role distinct from that of the known ErbB ligands.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

et al. 1999

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“…One can anticipate NRG2 to be a myeloma cell growth factor because NRG1 and NRG2 are closely related proteins that have the same specificity for ErbB receptors and have a HS-binding (Ig-like) domain (Carraway et al, 1997). NRG3 does not have this HS-binding Ig-like domain (Zhang et al, 1997) but we cannot exclude that it can also bind HSPGs. The role of NRG2 and NRG3 will deserve further studies.…”

Section: Discussionmentioning

confidence: 97%

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

et al. 2006

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The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro.To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-a were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) -neuregulin-1, amphiregulin, HB-EGF -promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10 5 molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

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“…These as well as other results, including downregulation of binding of EGF to EGFR by heregulin/NDF , suggest that ligand binding can induce a series of complex interactions, resulting from heterodimerization and/or transphosphorylation of speci®c members of the RTK I family by other members of the group. The recent cloning of two new heregulin genes, neuregulin-2 (Carraway III et al, 1997;Chang et al, 1997) and neuregulin-3 (Zhang et al, 1997), that have di erent RTK I speci®cities, adds further complexity to this ligand-receptor system. The mechanism of type I receptor homo or heterodimerization resulting from HRG binding in human epithelial as well as neural cells is currently the subject of intense investigation.…”

Section: Introductionmentioning

confidence: 99%

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Akita²,

et al. 1999

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The heregulins are a family of ligands with ability to induce phosphorylation of the p185 HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of di erentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the e ects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/ neu receptor, this report presents the use of several di erent assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo e ects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of ®ve di erent biologic assays in nine di erent cell lines, across two di erent epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We ®nd no evidence that heregulin has any growth-inhibitory e ects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself a ects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG.

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Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4

Cited by 357 publications

References 44 publications

Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

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