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. 2018 Mar 27;9:578. doi: 10.3389/fimmu.2018.00578

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Copyright © 2018 Guri, Nordmann and Roszik.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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mTOR signaling promotes anabolism. Receptor Tyrosine Kinases (RTKs)- Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase (PI3K) activated by growth factor (like insulin). PI3K generates phosphatidylinositol-3,4,5-trisphosphate (PIP3) from the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2). Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) counteracts PI3K activity (restoring PIP3 to PIP2). PIP3 recruits to the plasma membrane and activates phosphoinositide-dependent kinase 1 (PDK1) and AKT. PDK1 phosphorylates and activates AKT (pAKT-Thr308). pAKT-Thr308 phosphorylates and inhibits the TSC complex. The TSC complex, composed of tuberous sclerosis complex 1 (TSC1) and TSC2 and TRE2-BUB2-CDC16 domain family member 7 (TBC1D7), activates the lysosomal RAS homolog enriched in brain (RHEB). RHEB interacts with and activates mTORC1. mTORC1 comprises mTOR, mammalian lethal with sec-13 protein 8 (mLST8), and regulatory-associated protein of mammalian target of rapamycin (RAPTOR). mTORC1 can also be activated by nutrients (such as amino acids). Cellular energy status also regulates mTORC1 through AMPK-mediated TSC or RAPTOR phosphorylation. mTORC1 promotes anabolism, among others, through ribosomal protein S6 kinase (S6K), eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1), and blocks cellular catabolism through Unc-51-like kinase 1 (ULK1). Through S6K-mediated IRS1 phosphorylation, mTORC1 negatively regulates mTORC2-AKT signaling. Rapamycin and its analogs (so-called rapalogues) acutely inhibit mTORC1 allosterically. The ATP-site competitive inhibitor(s) potently block both mTORC1 and mTORC2 signaling. mTORC2 is also activated by RTKs, and consists of mTOR, mLST8, mammalian stress-activated map kinase-interacting protein 1 (mSIN1), and rapamycin-insensitive companion of mTOR (RICTOR). mTORC2 regulates the AGC kinase family members AKT, serum/glucocorticoid-regulated kinase (SGK), and protein kinase C (PKC). Prolonged rapamycin administration may block mTORC2 activity.