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NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling

Abstract

The intracellular mechanism(s) by which a cell determines the duration of extracellular signal–regulated kinase (ERK) activation is not well understood. We have investigated the role of STEP, a striatal-enriched tyrosine phosphatase, in the regulation of ERK activity in rat neurons. Glutamate-mediated activation of NMDA receptors leads to the rapid but transient phosphorylation of ERK in cultured neurons. Here we show that activation of NMDA receptors led to activation of STEP, which limited the duration of ERK activity as well as its translocation to the nucleus and its subsequent downstream nuclear signaling. In neurons, STEP is phosphorylated and inactive under basal conditions. NMDA-mediated influx of Ca2+, but not increased intracellular Ca2+ from other sources, leads to activation of the Ca2+-dependent phosphatase calcineurin and the dephosphorylation and activation of STEP. We have identified an important mechanism involved in the regulation of ERK activity in neurons that highlights the complex interplay between serine/threonine and tyrosine kinases and phosphatases.

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Figure 1: Glutamate stimulates transient activation and nuclear translocation of ERK2 in neurons.
Figure 2: Glutamate regulates the phosphorylation of STEP in neurons.
Figure 3: Dephosphorylation of STEP at the serine residue in the KIM domain.
Figure 4: Role of Ca2+ in the dephosphorylation of ERK2 and STEP.
Figure 5: NMDA receptor–mediated dephosphorylation of STEP61 and ERK2.
Figure 6: Effect of glutamate and KCl on the phosphorylation of ERK2, STEP and CREB.
Figure 7: Dephosphorylation of STEP61 and ERK2 is mediated by the Ca2+-dependent phosphatase calcineurin.
Figure 8: Tyrosine dephosphorylation and release of ERK2 by STEP.

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Acknowledgements

This work was supported by the National Institutes of Health grants NS35989, MH01527 and MH52711 (P.J.L.) and MH40899 and DA10044 (A.C.N.). We thank A. Bennett, J. Naegele, M. Picciotto and R. Poddar for their helpful comments on the manuscript.

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Correspondence to Paul J. Lombroso.

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Paul, S., Nairn, A., Wang, P. et al. NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nat Neurosci 6, 34–42 (2003). https://doi.org/10.1038/nn989

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