Cyclic AMP induces transactivation of the receptors for epidermal growth factor and nerve growth factor, thereby modulating activation of MAP kinase, Akt, and neurite outgrowth in PC12 cells.
2002 (English)In: J Biol Chem, ISSN 0021-9258, Vol. 277, no 46, 43623-30 p.Article in journal (Refereed) Published
In PC12 cells, a well studied model for neuronal differentiation, an elevation in the intracellular cAMP level increases cell survival, stimulates neurite outgrowth, and causes activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). Here we show that an increase in the intracellular cAMP concentration induces tyrosine phosphorylation of two receptor tyrosine kinases, i.e. the epidermal growth factor (EGF) receptor and the high affinity receptor for nerve growth factor (NGF), also termed Trk(A). cAMP-induced tyrosine phosphorylation of the EGF receptor is rapid and correlates with ERK1/2 activation. It occurs also in Panc-1, but not in human mesangial cells. cAMP-induced tyrosine phosphorylation of the NGF receptor is slower and correlates with Akt activation. Inhibition of EGF receptor tyrosine phosphorylation, but not of the NGF receptor, reduces cAMP-induced neurite outgrowth. Expression of dominant-negative Akt does not abolish cAMP-induced survival in serum-free media, but increases cAMP-induced ERK1/2 activation and neurite outgrowth. Together, our results demonstrate that cAMP induces dual signaling in PC12 cells: transactivation of the EGF receptor triggering the ERK1/2 pathway and neurite outgrowth; and transactivation of the NGF receptor promoting Akt activation and thereby modulating ERK1/2 activation and neurite outgrowth.
Place, publisher, year, edition, pages
2002. Vol. 277, no 46, 43623-30 p.
8-Bromo Cyclic Adenosine Monophosphate/metabolism, Animals, Apoptosis, Cell Death, Cell Division, Culture Media; Serum-Free/pharmacology, Cyclic AMP/*metabolism, DNA; Complementary/metabolism, Dose-Response Relationship; Drug, Enzyme Activation, Epidermal Growth Factor, Forskolin/pharmacology, Genes; Dominant, Immunoblotting, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1/metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases/metabolism, Neurons/*metabolism, PC12 Cells, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins/*metabolism, Proto-Oncogene Proteins c-akt, Rats, Receptor; Epidermal Growth Factor/*metabolism, Receptor; Nerve Growth Factor/*metabolism, Trans-Activation (Genetics), Transfection
IdentifiersURN: urn:nbn:se:uu:diva-10453PubMedID: 12218049OAI: oai:DiVA.org:uu-10453DiVA: diva2:38221