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Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3.

Vartanian T, Goodearl A, Viehöver A, Fischbach G - J. Cell Biol. (1997)

Bottom Line: We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3.Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers.The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor-inducing activity. Three signal transducing transmembrane receptors for neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

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Neuregulin induces a mobility shift in HER2 and HER3  and the rapid phosphorylation of a 180–190-kD protein in  Schwann cells. Schwann cells were cultured as described in Materials and Methods, treated with neuregulin for the times indicated  (control, 10 s, 1 min, 30 min, 1 h, 6 h, 12 h, and 24 h), and then lysed  with ice-cold lysis buffer. Total cell lysates were resolved by 5%  PAGE and transferred to PVDF membranes. HER2 and HER3  were visualized with polyclonal antisera, and tyrosine-phosphorylated proteins were visualized with the monoclonal antibody G410.
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Figure 5: Neuregulin induces a mobility shift in HER2 and HER3 and the rapid phosphorylation of a 180–190-kD protein in Schwann cells. Schwann cells were cultured as described in Materials and Methods, treated with neuregulin for the times indicated (control, 10 s, 1 min, 30 min, 1 h, 6 h, 12 h, and 24 h), and then lysed with ice-cold lysis buffer. Total cell lysates were resolved by 5% PAGE and transferred to PVDF membranes. HER2 and HER3 were visualized with polyclonal antisera, and tyrosine-phosphorylated proteins were visualized with the monoclonal antibody G410.

Mentions: We examined total lysates of Schwann cells and found that neuregulin induced the rapid tyrosine phosphorylation of a 170–190-kD protein detected 1 min after treatment, peaking in intensity at 30 min (Fig. 5). At the time of peak tyrosine phosphorylation, a mobility shift in the HER2 band was observed (Fig. 5). This suggests that the change in electrophoretic properties results from the increased phosphorylation, as has been noted with other proteins (27). After more prolonged treatment, the HER2 band migrated to its pretreatment mobility. Furthermore, the amount of HER2 in these total lysates had apparently decreased at later time points, perhaps reflecting ligand-dependent degradation (Fig. 5). Neuregulin also stimulates a mobility shift in the HER3 immunoreactive band over the same time course (Fig. 5). Unlike HER2 however, the intensity and mobility of the HER3 band is sustained for >12 h.


Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3.

Vartanian T, Goodearl A, Viehöver A, Fischbach G - J. Cell Biol. (1997)

Neuregulin induces a mobility shift in HER2 and HER3  and the rapid phosphorylation of a 180–190-kD protein in  Schwann cells. Schwann cells were cultured as described in Materials and Methods, treated with neuregulin for the times indicated  (control, 10 s, 1 min, 30 min, 1 h, 6 h, 12 h, and 24 h), and then lysed  with ice-cold lysis buffer. Total cell lysates were resolved by 5%  PAGE and transferred to PVDF membranes. HER2 and HER3  were visualized with polyclonal antisera, and tyrosine-phosphorylated proteins were visualized with the monoclonal antibody G410.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139859&req=5

Figure 5: Neuregulin induces a mobility shift in HER2 and HER3 and the rapid phosphorylation of a 180–190-kD protein in Schwann cells. Schwann cells were cultured as described in Materials and Methods, treated with neuregulin for the times indicated (control, 10 s, 1 min, 30 min, 1 h, 6 h, 12 h, and 24 h), and then lysed with ice-cold lysis buffer. Total cell lysates were resolved by 5% PAGE and transferred to PVDF membranes. HER2 and HER3 were visualized with polyclonal antisera, and tyrosine-phosphorylated proteins were visualized with the monoclonal antibody G410.
Mentions: We examined total lysates of Schwann cells and found that neuregulin induced the rapid tyrosine phosphorylation of a 170–190-kD protein detected 1 min after treatment, peaking in intensity at 30 min (Fig. 5). At the time of peak tyrosine phosphorylation, a mobility shift in the HER2 band was observed (Fig. 5). This suggests that the change in electrophoretic properties results from the increased phosphorylation, as has been noted with other proteins (27). After more prolonged treatment, the HER2 band migrated to its pretreatment mobility. Furthermore, the amount of HER2 in these total lysates had apparently decreased at later time points, perhaps reflecting ligand-dependent degradation (Fig. 5). Neuregulin also stimulates a mobility shift in the HER3 immunoreactive band over the same time course (Fig. 5). Unlike HER2 however, the intensity and mobility of the HER3 band is sustained for >12 h.

Bottom Line: We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3.Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers.The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
We are interested in the signaling between axons and glia that leads to myelination and maintenance of the myelin internode, and we have focused on the role of neuregulins and their receptors. Neuregulins are a family of ligands that includes heregulin, neu differentiation factor, glial growth factor, and the acetylcholine receptor-inducing activity. Three signal transducing transmembrane receptors for neuregulins, which bear significant homology to the EGF receptor, are currently known: HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4). We have found that oligodendrocite-type II astrocyte (O2A) progenitor cells and mature oligodendrocytes express HER2 and HER4 but no HER3. Schwann cells express HER2 and HER3 but little HER4. In O2A progenitor cells and oligodendrocytes, recombinant neuregulin induces the rapid tyrosine phosphorylation of only HER4. HER2 is not phosphorylated in cells of the oligodendrocyte lineage, but a physical interaction between HER2 and HER4 was detected in coimmunoprecipitation experiments. In Schwann cells, neuregulin induces the phosphorylation of both HER2 and HER3. Coimmunoprecipitation experiments indicate that receptor activation in Schwann cells results in the formation of HER2:HER3 heterodimers. Neuregulin localized immunocytochemically was present on neurites of cultured dorsal root ganglion neurons, and it was released into the medium in a form that promoted receptor tyrosine phosphorylation. Neuregulins therefore meet important criteria expected of molecules involved in axonal-glial signaling. The use of unique neuregulin receptor combinations in oligodendrocytes and Schwann cells likely results in recruitment of different signaling pathways and thus provides a basis for different biological responses.

Show MeSH
Related in: MedlinePlus