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

Nat Neurosci. 2003 Jan;6(1):34-42. doi: 10.1038/nn989.


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 Ca(2+), but not increased intracellular Ca(2+) from other sources, leads to activation of the Ca(2+)-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Brain / cytology
  • Brain / enzymology*
  • Calcineurin / metabolism
  • Calcineurin Inhibitors
  • Calcium / metabolism
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Fetus
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Phosphorylation
  • Pregnancy
  • Protein Tyrosine Phosphatases / drug effects
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • Calcineurin Inhibitors
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Mitogen-Activated Protein Kinases
  • Calcineurin
  • Protein Tyrosine Phosphatases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, rat
  • Calcium