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Negative regulation of mTOR activation by diacylglycerol kinases.

Publication ,  Journal Article
Gorentla, BK; Wan, C-K; Zhong, X-P
Published in: Blood
April 14, 2011

The engagement of TCR induces T-cell activation, which initiates multiple characteristic changes such as increase in cell size, cell division, and the production of cytokines and other effector molecules. The mammalian target of rapamycin (mTOR) regulates protein synthesis, transcription, cell survival, and autophagy. Critical roles of mTOR in T-cell activation and effector/memory differentiation have been revealed using chemical inhibitors or by genetic ablation of mTOR in T cells. However, the connection between mTOR signaling and other signaling cascades downstream of TCR is unclear. We demonstrate that diacylglycerol (DAG) and TCR engagement activate signaling in both mTOR complexes 1 and 2 through the activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mek1/2)-extracellular signal-regulated kinase 1/2 (Erk1/2)-activator protein 1 (AP-1), known collectively as the Ras-Mek1/2-Erk1/2-AP-1 pathway. Deficiency of RasGRP1 or inhibition of Mek1/2 activity drastically decreases TCR-induced mTOR activation, whereas constitutively active Ras or Mek1 promotes mTOR activation. Although constitutively active Akt promotes TCR-induced mTOR activation, such activation is attenuated by Mek1/2 inhibition. We demonstrated further that DAG kinases (DGKs) α and ζ, which terminate DAG-mediated signaling, synergistically inhibit TCR-induced mTOR activation by inhibiting the Ras-Mek1/2-Erk/12 pathway. These observations provide novel insights into the regulation of mTOR activation.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

April 14, 2011

Volume

117

Issue

15

Start / End Page

4022 / 4031

Location

United States

Related Subject Headings

  • ras Proteins
  • Transcription Factor AP-1
  • Thymus Gland
  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Receptors, Antigen, T-Cell
  • Phosphatidylinositol 3-Kinases
  • Mice, Mutant Strains
  • Mice
  • MAP Kinase Signaling System
 

Citation

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MLA
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Gorentla, B. K., Wan, C.-K., & Zhong, X.-P. (2011). Negative regulation of mTOR activation by diacylglycerol kinases. Blood, 117(15), 4022–4031. https://doi.org/10.1182/blood-2010-08-300731
Gorentla, Balachandra K., Chi-Keung Wan, and Xiao-Ping Zhong. “Negative regulation of mTOR activation by diacylglycerol kinases.Blood 117, no. 15 (April 14, 2011): 4022–31. https://doi.org/10.1182/blood-2010-08-300731.
Gorentla BK, Wan C-K, Zhong X-P. Negative regulation of mTOR activation by diacylglycerol kinases. Blood. 2011 Apr 14;117(15):4022–31.
Gorentla, Balachandra K., et al. “Negative regulation of mTOR activation by diacylglycerol kinases.Blood, vol. 117, no. 15, Apr. 2011, pp. 4022–31. Pubmed, doi:10.1182/blood-2010-08-300731.
Gorentla BK, Wan C-K, Zhong X-P. Negative regulation of mTOR activation by diacylglycerol kinases. Blood. 2011 Apr 14;117(15):4022–4031.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

April 14, 2011

Volume

117

Issue

15

Start / End Page

4022 / 4031

Location

United States

Related Subject Headings

  • ras Proteins
  • Transcription Factor AP-1
  • Thymus Gland
  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Receptors, Antigen, T-Cell
  • Phosphatidylinositol 3-Kinases
  • Mice, Mutant Strains
  • Mice
  • MAP Kinase Signaling System