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

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. © 2006 Wiley‐Liss, Inc.