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Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt

Brittany L Dunkerly-Eyring1,2, Shi Pan1, Miguel Pinilla-Vera1

  • 1Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Life Science Alliance
|March 15, 2022
PubMed

Insights

Tuberous sclerosis complex-2 (TSC2) phosphorylation at Serine 1364 specifically controls extracellular signal-regulated kinase (ERK1/2)-mediated mammalian target of rapamycin complex 1 (mTORC1) activation, not Akt-dependent pathways. This finding offers a targeted approach to modulate mTORC1 signaling.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Biochemistry

Background:

  • Tuberous sclerosis complex-2 (TSC2) is a key negative regulator of mTORC1 signaling.
  • Phosphorylation of TSC2 by Akt and ERK1/2 kinases activates mTORC1.
  • Serine 1364 (S1364) on TSC2 is a critical modification site influencing mTORC1 activity.

Purpose of the Study:

  • To investigate the specific role of TSC2 S1364 phosphorylation in modulating mTORC1 activation by different signaling pathways.
  • To differentiate between ERK1/2-dependent and Akt-dependent TSC2-mTORC1 activation.
  • To determine the in vivo relevance of S1364 modifications in metabolic conditions.

Main Methods:

  • Utilized phospho-mimetic (S1364E) and phospho-silenced (S1364A) TSC2 mutations in cellular models.
  • Stimulated mTORC1 signaling with various agonists including Endothelin-1, insulin, PDGF, and thrombin.
  • Assessed mTORC1 activation in response to S1364 modifications under basal and stimulated conditions, including in vivo models of diet-induced obesity.

Main Results:

  • TSC2 S1364 modification specifically impacts ERK1/2-dependent mTORC1 activation, not Akt-dependent pathways.
  • Endothelin-1 and thrombin-induced mTORC1 activation were modulated by S1364 mutations, while insulin and PDGF effects were unaltered.
  • S1364 modifications showed negligible effects on mTORC1 regulation by energy status and were unaltered in diet-induced obesity and diabetes models in vivo.

Conclusions:

  • TSC2 S1364 phosphorylation provides a selective mechanism for controlling ERK1/2-mediated mTORC1 activation.
  • This site offers a means to genetically distinguish pathological mTORC1 stimuli from physiological ones.
  • The findings highlight the pathway-specific role of TSC2 S1364 in mTORC1 regulation.

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