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 exposure 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), but not with other mitogenic factors, transiently increases intracellular cyclic AMP (cAMP), with maximal elevation at the G0/G1 boundary. The cAMP-dependent protein kinase (PKA) inhibitor H-89 strongly antagonized GGF- and neuron-induced Schwann cell proliferation, with maximum inhibition observed at G0/G1. H-89 also inhibited Schwann cell proliferation induced by growth factors that did not increase intracellular cAMP. Stimulation of Schwann cells with rhGGF2 resulted in 70-fold activation of MAP kinase; forskolin treatment resulted in a 50% decrease in MAP kinase activity but did not alter Raf-1 phosphorylation on Ser-43. These results demonstrate that the MAP kinase cascade represents an intersection between receptor tyrosine kinase and cAMP signaling pathways in Schwann cells and that PKA plays a critical role in Schwann cell cycle progression.
Kim
H A
HA
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Ohio 45267-0521, USA.
DeClue
J E
JE
Ratner
N
N
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020904:Glia Maturation Factor; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D020880:Neuregulins; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012583:Schwann Cells / Q000166:cytology*; D013268:Stimulation, Chemical; D013449:Sulfonamides
D004791:Enzyme Inhibitors; D020904:Glia Maturation Factor; D006023:Glycoproteins; D007546:Isoquinolines; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020880:Neuregulins; D011994:Recombinant Proteins; D013449:Sulfonamides; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide