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ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling

Jeremiah N Winter1, Leonard S Jefferson, Scot R Kimball

  • 1Dept. of Cellular and Molecular Physiology, The Pennsylvania State University, College of Medicine, 500 University Dr., Hershey, PA 17033, USA.

American Journal of Physiology. Cell Physiology
|February 4, 2011
PubMed

Insights

Akt and ERK signaling synergistically activate mTORC1 by phosphorylating distinct sites on TSC2, enhancing its inhibitory function. Leucine stimulation of mTORC1 signaling occurs independently of TSC2.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Metabolic Regulation

Background:

  • The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth and metabolism.
  • mTORC1 activity is modulated by upstream signaling pathways, including Akt and extracellular-regulated kinase (ERK).
  • Tuberous sclerosis complex 2 (TSC2) is a GTPase activator protein (GAP) that inhibits mTORC1 and is phosphorylated by Akt and ERK.

Purpose of the Study:

  • To investigate the synergistic activation of mTORC1 signaling by Akt and ERK.
  • To determine if Akt and ERK signaling pathways converge on TSC2.
  • To elucidate the mechanism of leucine-induced mTORC1 stimulation.

Main Methods:

  • Investigated the synergistic effects of Akt and ERK activation on mTORC1 signaling.
  • Examined the convergence of Akt and ERK pathways on TSC2.
  • Analyzed the phosphorylation sites on TSC2 targeted by Akt and ERK.
  • Studied leucine-induced mTORC1 activation.

Main Results:

  • Akt and ERK signaling synergistically promote mTORC1 signaling.
  • Evidence shows Akt and ERK signaling pathways converge on TSC2.
  • Akt and ERK phosphorylate distinct residues on TSC2, leading to enhanced inhibition of its GAP activity.
  • Leucine-induced stimulation of mTORC1 signaling occurs via a mechanism independent of TSC2 and the Akt/ERK pathways.

Conclusions:

  • Akt and ERK signaling synergistically enhance mTORC1 activation through distinct phosphorylation sites on TSC2.
  • This synergistic action magnifies mTORC1 signaling compared to individual pathway activation.
  • Leucine stimulates mTORC1 through a separate pathway, not involving TSC2.

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