CAMP-DEPENDENT PROTEIN-KINASE-A IS REQUIRED FOR SCHWANN-CELL GROWTH -INTERACTIONS BETWEEN THE CAMP AND NEUREGULIN TYROSINE KINASE PATHWAYS

Schwann cell proliferation is stimulated by contact with neurons or ex posure to growth factor ligands for tyrosine kinase receptors, effects of which are potentiated by cAMP. Here we show that treatment of rat Schwann cells with recombinant human glial growth factor 2 (rhGGF2), b ut not with other mitogenic factors, transiently increases intracellul ar cyclic AMP (cAMP), with maximal elevation at the G0/G1 boundary. Th e cAMP-dependent protein kinase (PKA) inhibitor H-89 strongly antagoni zed GGF- and neuron-induced Schwann cell proliferation, with maximum i nhibition observed at G0/G1. H-89 also inhibited Schwann cell prolifer ation induced by growth factors that did not increase intracellular cA MP, Stimulation of Schwann cells with rhGGF2 resulted in 70-fold activ ation of MAP kinase; forskolin treatment resulted in a 50% decrease in MAP kinase activity but did nor alter Raf-l phosphorylation on Ser-43 . These results demonstrate that the MAP kinase cascade represents an intersection between receptor tyrosine kinase and cAMP signaling pathw ays in Schwann cells and that PI(A plays a critical role in Schwann ce ll cycle progression. (C) 1997 Wiley-Liss, Inc.