Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways

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Updated: Oct 30, 2026

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
09:32

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

Published on: June 15, 2017

J Xing1, J M Kornhauser, Z Xia

  • 1Department of Neurobiology, Harvard Medical School, Children's Hospital, Boston, Massachusetts 02115, USA.

Molecular and Cellular Biology
|April 7, 1998
PubMed

Insights

Nerve growth factor (NGF) activates two distinct mitogen-activated protein kinase (MAPK) pathways, extracellular signal-regulated kinase/ribosomal S6 kinase (ERK/RSK) and p38/MAPK-activated protein kinase 2 (MAPKAP kinase 2). Both pathways are crucial for phosphorylating the transcription factor CREB at serine 133, leading to gene activation.

Area of Science:

  • Cellular signaling and molecular biology
  • Neuroscience and signal transduction

Background:

  • Growth factors like Nerve Growth Factor (NGF) regulate gene expression by activating transcription factors.
  • The transcription factor CREB (cAMP response element-binding protein) is a key mediator of cellular responses to various stimuli, including growth factors.
  • Understanding the precise signaling cascades that lead to CREB activation is crucial for deciphering gene regulation.

Purpose of the Study:

  • To elucidate the specific signaling pathways by which NGF induces the phosphorylation and activation of CREB at serine 133.
  • To determine the contribution of different mitogen-activated protein kinase (MAPK) pathways in mediating NGF-induced CREB activation.

Main Methods:

  • Investigated NGF-induced signaling using in vitro and in vivo assays.
  • Utilized specific inhibitors to block the extracellular signal-regulated kinase (ERK)/ribosomal S6 kinase (RSK) pathway and the p38 MAPK/MAPK-activated protein kinase 2 (MAPKAP kinase 2) pathway.
  • Assessed the phosphorylation of CREB at serine 133 in response to NGF and pathway inhibition.

Main Results:

  • NGF activates both the ERK/RSK and p38/MAPKAP kinase 2 signaling pathways.
  • Both pathways independently contribute to the phosphorylation of CREB at serine 133.
  • Complete inhibition of both pathways abolished NGF-induced CREB phosphorylation, indicating their synergistic role.

Conclusions:

  • NGF employs two parallel MAPK pathways, ERK/RSK and p38/MAPKAP kinase 2, to achieve CREB phosphorylation at Ser-133.
  • These findings reveal a complex but coordinated signaling mechanism for NGF-mediated gene activation.
  • The identified pathways are critical for coupling extracellular NGF signals to nuclear events, including the activation of immediate-early genes.

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