Negative regulation of mTOR activation by diacylglycerol kinases

• Published in: Blood 2011-04, Vol.117 (15), p.4022-4031
• Main Authors: Gorentla, Balachandra K., Wan, Chi-Keung, Zhong, Xiao-Ping
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; Diacylglycerol Kinase - genetics; Diacylglycerol Kinase - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Hematologic and hematopoietic diseases; Immunobiology; Immunologic Memory - physiology; Lymphocyte Activation - physiology; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - metabolism; MAP Kinase Signaling System - immunology; Medical sciences; Mice; Mice, Mutant Strains; Phosphatidylinositol 3-Kinases - metabolism; ras Proteins - metabolism; Receptors, Antigen, T-Cell - metabolism; T-Lymphocytes - enzymology; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription Factor AP-1 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-08-300731

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.