Cyclic AMP synergistically enhances neuregulin‐dependent ERK and Akt activation and cell cycle progression in Schwann cells

Abstract

The elevation of intracellular cAMP synergistically enhances the neuregulin-dependent proliferation of cultured Schwann cells (SCs); however, the mechanism by which this occurs has not been completely defined. To better understand this mechanism, we investigated the effect of cAMP on the activation of the extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)-Akt (PKB) pathways by heregulin, a member of the neuregulin family. Using primary cultures of adult SCs, we demonstrated that the adenylyl cyclase activator, forskolin, enhanced heregulin-dependent SC proliferation by reducing the time required for S-phase entry. When cAMP levels were increased, using either forskolin or a cell permeable analogue of cAMP, the heregulin-induced phosphorylation of ERK was converted from transient to sustained and the heregulin-induced phosphorylation of Akt was synergistically increased. Consistent with these observations, studies in which inhibitors of MEK, the upstream stimulating ERK kinase, and PI3-K were administered at different times following the onset of stimulation indicated that sustained high levels of both MEK/ERK and PI3-K/Akt activity before S-phase initiation were essential for S-phase entry. Overall, these novel results indicate that in neuregulin-stimulated SCs the activation of cAMP-mediated pathways accelerates G1-S progression by prolonging ERK activation and concurrently enhancing Akt activation.

Extracellular Signal-regulated Kinase Activation Is Required for Serine 727 Phosphorylation of STAT3 in Schwann Cells in vitro and in vivo

“…Furthermore, the nuclear transport of serine phosphorylated STAT3 was not observed following NRG treatment. It may be possible that serine phosphorylated STAT3 by NRG may play a cytoplasmic function, as was reported previously (Ng et al, 2006a) or NRG may induce genes with a very low level of serine phosphorylated STAT3 in the nucleus (undetectable level with the immunostaining method). Recently, Ng et al (2006b) reported that nerve growth factor stimulates the expression of STAT3 target genes such as JunB and egr-1 by inducing solely via the induction of serine phosphorylation of STAT3 in PC12 pheochromocytoma cells.…”

“…For example, cytokines such as IL-6 could activate ERK in SCs as we have demonstrated in other studeies. The ERK activation by multiple ligands after nerve injury has been suggested to be associated with the initiation of demyelination and proliferation (Harrisingh et al, 2004;Monje et al, 2006), two important characteristics of dedifferentiation, of SCs. However, the molecular mechanism underlying the function of ERK in dedifferentiation of SCs remains largely uncharacterized.…”

Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

“…For example, elevation of intracellular cAMP prolongs the activation of ERK by soluble NRG1 and increases the magnitude of NRG1 induced Akt phosphorylation (43). These effects were shown to occur through PKA-dependent modulation of signaling from the neuregulin receptor complex ErbB2/3.…”

“…These effects were shown to occur through PKA-dependent modulation of signaling from the neuregulin receptor complex ErbB2/3. The cAMP-mediated alterations in NRG1 signaling resulted in a substantial enhancement of Schwann cell proliferation (43). Therefore, cAMP-mediated signaling modulates NRG1 signaling at multiple levels, including the receptor complex (44) and the p65 subunit of NF-B (5).…”

Protein Kinase A-Induced Phosphorylation of the p65 Subunit of Nuclear Factor-κB Promotes Schwann Cell Differentiation into a Myelinating Phenotype

“…Increasing cAMP alone, in the absence of serum or exogenous growth factors, does not increase proliferation but induces markers of differentiation, e.g., P0 (Morgan et al, 1991). However, when cAMP is elevated in concert with exposure to serum or growth factors, such as neuregulin, then a synergistic effect is seen and there is robust cell proliferation (Lemke and Brockes, 1984;Stewart et al, 1991;Kim et al, 1997;Rahmatullah et al, 1998;Monje et al, 2006).…”