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Published on: October 23, 2018

Negative regulation of mTOR activation by diacylglycerol kinases

Balachandra K Gorentla1, Chi-Keung Wan, Xiao-Ping Zhong

  • 1Department of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC, USA.

Blood
|February 12, 2011
PubMed

Insights

T-cell activation via T-cell receptor (TCR) engagement involves mammalian target of rapamycin (mTOR) signaling. This study reveals the Ras-Mek1/2-Erk1/2-AP-1 pathway links TCR signals to mTOR activation, with DAG kinases regulating this process.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • T-cell activation by T-cell receptor (TCR) engagement triggers significant cellular changes.
  • Mammalian target of rapamycin (mTOR) is crucial for T-cell activation and differentiation.
  • The precise signaling pathways connecting TCR engagement to mTOR remain incompletely understood.

Purpose of the Study:

  • To elucidate the signaling cascades downstream of TCR engagement that regulate mTOR activation.
  • To investigate the role of the Ras-Mek1/2-Erk1/2-AP-1 pathway in TCR-induced mTOR signaling.
  • To determine the impact of diacylglycerol (DAG) and DAG kinases (DGKs) on mTOR activation.

Main Methods:

  • Investigated TCR-induced signaling in T cells.
  • Utilized genetic manipulation (RasGRP1 deficiency) and pharmacological inhibitors (Mek1/2 inhibitors).
  • Assessed the effects of constitutively active signaling components (Ras, Mek1, Akt) and DGKs on mTOR activation.

Main Results:

  • TCR engagement and diacylglycerol (DAG) activate mTORC1 and mTORC2 via the Ras-Mek1/2-Erk1/2-AP-1 pathway.
  • RasGRP1 deficiency or Mek1/2 inhibition significantly impairs TCR-induced mTOR activation.
  • Constitutively active Ras or Mek1 enhances mTOR activation, while active Akt's effect is partially dependent on Mek1/2.
  • DAG kinases (DGKs) α and ζ inhibit TCR-induced mTOR activation by suppressing the Ras-Mek1/2-Erk1/2-AP-1 pathway.

Conclusions:

  • The Ras-Mek1/2-Erk1/2-AP-1 pathway is a key mediator of TCR-induced mTOR activation.
  • DAG signaling, modulated by DGKs, plays a critical role in regulating mTOR activation downstream of TCR.
  • These findings offer new insights into the intricate regulation of mTOR signaling in T cells.

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