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Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt

C Rommel1, B A Clarke, S Zimmermann

  • 1Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.

Science (New York, N.Y.)
|November 27, 1999
PubMed

Insights

The phosphatidylinositol 3-kinase (PI3K)-Akt pathway inhibits the Raf-MEK-ERK pathway in differentiated muscle cells, but not in precursors. This stage-specific inhibition involves Akt complex formation with Raf, suggesting unique mediators.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Muscle Physiology

Background:

  • Extracellular signals activate both the Raf-MEK-ERK and PI3K-Akt pathways simultaneously.
  • These two major signaling cascades have opposing roles in regulating muscle cell hypertrophy.
  • The PI3K-Akt pathway is known to cross-regulate and inhibit the Raf-MEK-ERK pathway.

Purpose of the Study:

  • To investigate the differential regulation of the Raf-MEK-ERK pathway by the PI3K-Akt pathway.
  • To determine the role of cellular differentiation state in the cross-talk between these signaling pathways.
  • To elucidate the molecular mechanism underlying the inhibitory interaction between Akt and Raf.

Main Methods:

  • Analysis of simultaneous activation of Raf-MEK-ERK and PI3K-Akt signaling pathways.
  • Assessment of pathway cross-regulation in differentiated myotubes versus myoblast precursors.
  • Investigation of Akt complex formation with Raf in relation to inhibitory activity.

Main Results:

  • Akt activation inhibited the Raf-MEK-ERK pathway specifically in differentiated myotubes, not in myoblast precursors.
  • This stage-specific inhibition correlated with the ability of Akt to form a complex with Raf.
  • Evidence suggests the existence of differentially expressed mediators responsible for the inhibitory Akt-Raf complex.

Conclusions:

  • The inhibitory cross-talk between the PI3K-Akt and Raf-MEK-ERK pathways is dependent on the muscle cell differentiation state.
  • Akt's ability to inhibit Raf-MEK-ERK signaling is mediated by its interaction with Raf, which is cell-stage specific.
  • These findings highlight the complexity of muscle cell hypertrophy regulation and suggest novel therapeutic targets.

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