ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1.
The classical mitogen-activated protein kinase (MAPK; also known as extracellular-signal-regulated kinase), ERK cascade has been shown to have a crucial role in cell proliferation and differentiation. In PC12 cells, sustained activation of ERK induced by nerve-growth factor (NGF) is essential for neuronal differentiation. However, downstream targets of ERK that are essential for neuronal differentiation have not been defined. Here we show that NGF induces strong, sustained expression of p35, the neuron-specific activator of cyclin-dependent kinase 5 (Cdk5), through activation of the ERK pathway. The induced kinase activity of Cdk5 is required for NGF-induced neurite outgrowth. Our results indicate that sustained activation of ERK is necessary and sufficient for strong induction of p35. Furthermore, the transcription factor Egr1, is induced by NGF through the ERK pathway and mediates induction of p35 by ERK. Our results thus define an essential signalling pathway, downstream of ERK/MAPK, that leads to neuronal differentiation.
Harada
T
T
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Morooka
T
T
Ogawa
S
S
Nishida
E
E
D000818:Animals; D000831:Animals, Newborn; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins; D015151:Immunoblotting; D008074:Lipoproteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D020932:Nerve Growth Factor; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010770:Phosphotransferases; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D001425:Bacterial Outer Membrane Proteins; C492235:Cdk5r1 protein, rat; D002867:Chromones; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D017874:Immediate-Early Proteins; D008074:Lipoproteins; D009025:Morpholines; D011725:Pyridines; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020932:Nerve Growth Factor; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one