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Down-regulation of the PI3-kinase/Akt pathway by ERK MAP kinase in growth factor signaling

Hideko Hayashi1, Yoshiki Tsuchiya, Kei Nakayama

  • 1Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|August 12, 2008
PubMed

Insights

Inhibiting the ERK pathway boosts Akt phosphorylation via Ras/PI3-kinase, revealing ERK negatively regulates this signaling in response to growth factors.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Cancer research

Background:

  • Extracellular signal-regulated kinase (ERK) MAP kinase and phosphoinositide 3-kinase (PI3K)/Akt pathways are crucial for cell growth and survival.
  • The intricate crosstalk between ERK and PI3K/Akt pathways remains incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory relationship between the ERK and PI3K/Akt signaling pathways.
  • To investigate how modulating ERK activity impacts Akt phosphorylation and downstream signaling.

Main Methods:

  • Utilized MEK inhibitors (U0126, PD98059) to block ERK pathway activity.
  • Assessed Akt phosphorylation at Thr308 and Ser473 sites.
  • Employed PI3-kinase inhibitor (LY294002) and measured Ras activity.

Main Results:

  • MEK inhibition significantly enhanced epidermal growth factor (EGF)- and fibroblast growth factor (FGF)-induced Akt phosphorylation.
  • Hyperactivation of the ERK pathway attenuated EGF- and FGF-induced Akt phosphorylation.
  • Enhanced Akt phosphorylation upon ERK inhibition was dependent on PI3-kinase and linked to increased Ras activity.

Conclusions:

  • The ERK pathway negatively modulates the PI3K/Akt pathway during growth factor stimulation.
  • ERK pathway inhibition potentiates Akt activation through the Ras/PI3-kinase signaling axis.
  • Findings provide critical insights into the complex interplay of key cell signaling pathways in cellular regulation.

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