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PRAS40: target or modulator of mTORC1 signalling and insulin action?

Emmani B M Nascimento1, D Margriet Ouwens

  • 1Department of Molecular Cell Biology, Section Signal Transduction and Ageing, Leiden University Medical Centre, Leiden, The Netherlands.

Archives of Physiology and Biochemistry
|June 2, 2009
PubMed

Insights

Proline-rich Akt substrate of 40-kDa (PRAS40) regulates the mTORC1 pathway. Phosphorylation by PKB/Akt and mTORC1 disrupts this inhibition, impacting type 2 diabetes and cancer.

Area of Science:

  • Molecular Biology
  • Cellular Signalling
  • Biochemistry

Background:

  • Dysregulation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR) signalling is common in type 2 diabetes and cancer.
  • Proline-rich Akt substrate of 40-kDa (PRAS40) acts as a key regulator at the convergence of PKB/Akt and mTOR pathways.
  • PRAS40's interaction with mTOR complex 1 (mTORC1) inhibits mTORC1 activity, playing a crucial role in cellular regulation.

Purpose of the Study:

  • To review the signalling pathways governing PRAS40 phosphorylation.
  • To elucidate the dual role of PRAS40 as both a substrate and an inhibitor of mTORC1.
  • To examine PRAS40's function in physiological states and its implications in pathological conditions like insulin resistance and cancer.

Main Methods:

  • Literature review of signalling pathways.
  • Analysis of PRAS40 phosphorylation mechanisms.
  • Examination of PRAS40's regulatory role in mTORC1 activity.

Main Results:

  • PKB/Akt and mTORC1 signalling pathways regulate PRAS40 phosphorylation.
  • Phosphorylation of PRAS40 by PKB/Akt and mTORC1 dissociates it from mTORC1.
  • This dissociation relieves PRAS40-mediated inhibition of mTORC1 activity.

Conclusions:

  • PRAS40 acts as a crucial inhibitory rheostat for mTORC1.
  • Understanding PRAS40 phosphorylation is vital for comprehending mTORC1 regulation in health and disease.
  • Targeting the PRAS40-mTORC1 axis may offer therapeutic strategies for type 2 diabetes and cancer.

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