title: Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects.
abstract: Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB). This signaling cascade is frequently upregulated due to loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK. mTORC2 plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. Both complexes control each other as Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Another significant component of mTORC2 is Sin1, which is crucial for mTORC2 complex formation and function. Allosteric inhibitors of mTOR, rapamycin and rapalogs, have essentially been ineffective in clinical trials of patients with GB due to their incomplete inhibition of mTORC1 or unexpected activation of mTOR via the loss of negative feedback loops. Novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6KSer235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKTSer473. Furthermore, proliferation and self-renewal of GB cancer stem cells are effectively targetable by these novel mTORC1 and mTORC2 inhibitors. Therefore, the effectiveness of inhibitors of mTOR complexes can be estimated by their ability to suppress both mTORC1 and 2 and their ability to impede both cell proliferation and migration.
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States. Electronic address: meena_jhanwar@nymc.edu.
authors.forename: Meena
authors.initials: M
authors.lastname: Jhanwar-Uniyal
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States.
authors.forename: Anubhav G
authors.initials: AG
authors.lastname: Amin
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States.
authors.forename: Jared B
authors.initials: JB
authors.lastname: Cooper
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Das
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States.
authors.forename: Meic H
authors.initials: MH
authors.lastname: Schmidt
authors.affiliation: Department of Neurosurgery, New York Medical College, Member of the Touro College and University System, Valhalla, NY 10595, United States.
authors.forename: Raj
authors.initials: R
authors.lastname: Murali
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D020123:Sirolimus; C515074:ridaforolimus; C401859:temsirolimus; C494929:PTEN protein, human; C572919:PP242
keywords: Akt; Stem cell; mTOR; mTORC1; mTORC2