The Neuron-Glia Signal β Neuregulin Induces Sustained CREB Phosphorylation on Ser-133 in Cultured Rat Schwann Cells

Abstract

β neuregulins (also called NDF, GGF, ARIA, and heregulins) are neuron-derived molecules that are likely to be responsible for Schwann cell precursor survival, proliferation, and maturationin vivoandin vitro.Although the receptors to which β neuregulins bind have been defined, little is known about the transcription factors these important ligands activate. Using antibodies, quantitative imaging methods and Western blotting, we show that β neuregulin induces a high level of phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) on Ser-133 in cultured rat Schwann cells and that the phosphorylation is prolonged over several hours. In contrast, neurotrophins, CNTF, FGF-2, EGF, and TGFβ induce little or no phosphorylation of CREB despite the fact that receptors for these factors are present on Schwann cells. As expected CREB phosphorylation was detected following cAMP elevation, and it was also induced by elevation of cytoplasmic Ca2+, endothelin 1, and PDGF-BB. The signal was lower than that seen in response to β neuregulin, and transient, unlike the sustained CREB activation induced by β neuregulin. Our results suggest that the sustained phosphorylation of CREB on Ser-133 may contribute to the broad spectrum of effects that β neuregulins have on cells of the Schwann cell lineage and that the CREB pathway may be important for transduction of neuregulin signals in Schwann cells.