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The adaptor protein p66Shc inhibits mTOR-dependent anabolic metabolism

Mohamed A Soliman1, Anas M Abdel Rahman, Dudley W Lamming

  • 11Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

Science Signaling
|February 20, 2014
PubMed

Insights

The p66Shc protein limits glucose metabolism and anabolic processes. Its absence enhances glycolysis and promotes the Warburg effect, suggesting a role in metabolic regulation.

Area of Science:

  • Cellular metabolism
  • Molecular signaling pathways
  • Obesity and diabetes research

Background:

  • Adaptor proteins are crucial for linking cell surface receptors to intracellular signaling.
  • The Shc1 protein family, including p66Shc, plays a role in receptor tyrosine kinase signaling.
  • Mice lacking p66Shc exhibit resistance to diabetes and obesity.

Purpose of the Study:

  • To investigate the role of p66Shc in regulating cellular glucose metabolism.
  • To determine if p66Shc influences the Warburg effect and anabolic metabolism.
  • To elucidate the signaling pathways, such as mTOR, involved in p66Shc's metabolic effects.

Main Methods:

  • Quantitative mass spectrometry to analyze metabolic changes in p66Shc deficient mice.
  • Assessment of glycolysis and glucose carbon allocation into anabolic pathways.
  • Pharmacological inhibition of the mammalian target of rapamycin (mTOR) pathway using rapamycin.

Main Results:

  • p66Shc was found to inhibit glucose metabolism.
  • p66Shc deficiency led to enhanced glycolysis and increased carbon flux into anabolic metabolism, characteristic of the Warburg effect.
  • Inhibition of mTOR reversed the enhanced glycolysis observed in p66Shc deficient mice.

Conclusions:

  • p66Shc acts as a critical inhibitor of glucose uptake and metabolism.
  • p66Shc antagonizes insulin and mTOR signaling pathways.
  • p66Shc plays a significant inhibitory role in anabolic metabolism, impacting metabolic diseases.

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