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ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1

Abstract

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.

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Figure 1: NGF induces expression of p35 and activation of Cdk5.
Figure 2: Inhibition of Cdk5 blocks NGF-induced neurite outgrowth.
Figure 3: Inhibition of the ERK pathway blocks p35 expression induced by NGF.
Figure 4: Expression of constitutively active MEK induces p35 expression.
Figure 5: Sustained activation of ERK is required for strong induction of p35 by NGF.
Figure 6: Egr1 mediates induction of p35 by the ERK pathway.
Figure 7: BDNF induces p35 expression through the ERK pathway in cerebellar granule cells.

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Acknowledgements

We thank H. Hanafusa, M. Adachi and other members of our laboratory for technical comments and helpful discussions. This work was supported by grants from the Ministry of Education, Science and Culture of Japan (to E.N.).

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Correspondence to Eisuke Nishida.

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Harada, T., Morooka, T., Ogawa, S. et al. ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat Cell Biol 3, 453–459 (2001). https://doi.org/10.1038/35074516

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