Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells.

TY - JOUR

T1 - Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells.

AU - Frödin, M

AU - Peraldi, P

AU - Van Obberghen, E

N1 - Keywords: Amino Acid Sequence; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cyclic AMP; Enzyme Activation; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Molecular Sequence Data; Nerve Growth Factors; Neurites; Neuropeptides; Neurotransmitter Agents; PC12 Cells; Phosphorylation; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats

PY - 1994

Y1 - 1994

N2 - Mitogen-activated protein (MAP) kinases are activated in response to a large variety of extracellular signals, including growth factors, hormones, and neurotransmitters, which activate distinct intracellular signaling pathways. Their activation by the cAMP-dependent pathway, however, has not been reported. In rat pheochromocytoma PC12 cells, we demonstrate here a stimulation of the MAP kinase isozyme extracellular signal-regulated kinase 1 (ERK1) following elevation of intracellular cAMP after exposure of the cells to isobutylmethylxanthine, cholera toxin, forskolin, or cAMP-analogues. cAMP acted synergistically with phorbol ester, an activator of protein kinase C, in the stimulation of ERK1. In accordance with this observation, the peptide neurotransmitter pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), which stimulates cAMP production as well as phosphatidylinositol breakdown in PC12 cells, was an efficient activator of ERK1. In combination with various growth factors, cAMP acted in a more than additive manner on ERK1 activity. Elevation of intracellular cAMP increased in vivo 32P-labeling of ERK1, suggesting that cAMP stimulated ERK1 by activating MAP kinase kinase, an immediate upstream activator of ERK1 in the MAP kinase cascade. Supporting this view, forskolin and a cAMP analogue were found to increase the activity of MAP kinase kinase in PC12 cells, alone as well as in combination with phorbol ester. PACAP38 also stimulated in vivo 32P-labeling of ERK1 and MAP kinase kinase activity. Finally, cAMP or PACAP38 increased by 3-fold nerve growth factor-stimulated neurite formation in PC12 cells, which may be correlated with the potentiating effect of these agents on nerve growth factor-stimulated ERK1 activity.

AB - Mitogen-activated protein (MAP) kinases are activated in response to a large variety of extracellular signals, including growth factors, hormones, and neurotransmitters, which activate distinct intracellular signaling pathways. Their activation by the cAMP-dependent pathway, however, has not been reported. In rat pheochromocytoma PC12 cells, we demonstrate here a stimulation of the MAP kinase isozyme extracellular signal-regulated kinase 1 (ERK1) following elevation of intracellular cAMP after exposure of the cells to isobutylmethylxanthine, cholera toxin, forskolin, or cAMP-analogues. cAMP acted synergistically with phorbol ester, an activator of protein kinase C, in the stimulation of ERK1. In accordance with this observation, the peptide neurotransmitter pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), which stimulates cAMP production as well as phosphatidylinositol breakdown in PC12 cells, was an efficient activator of ERK1. In combination with various growth factors, cAMP acted in a more than additive manner on ERK1 activity. Elevation of intracellular cAMP increased in vivo 32P-labeling of ERK1, suggesting that cAMP stimulated ERK1 by activating MAP kinase kinase, an immediate upstream activator of ERK1 in the MAP kinase cascade. Supporting this view, forskolin and a cAMP analogue were found to increase the activity of MAP kinase kinase in PC12 cells, alone as well as in combination with phorbol ester. PACAP38 also stimulated in vivo 32P-labeling of ERK1 and MAP kinase kinase activity. Finally, cAMP or PACAP38 increased by 3-fold nerve growth factor-stimulated neurite formation in PC12 cells, which may be correlated with the potentiating effect of these agents on nerve growth factor-stimulated ERK1 activity.

M3 - Journal article

C2 - 7907091

SN - 0021-9258

VL - 269

SP - 6207

EP - 6214

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 8

ER -