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.

• 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.

Nyckelord

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

Publikations- och innehållstyp

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