Mammalian target of rapamycin (mTOR) network

The mammalian target of rapamycin (mTOR) network. mTOR is a central component of the phosphoinositide 3′ kinase/protein kinase B (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation. The mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. mTORC1 also contains raptor, MLST8, and praline-rich Akt substrate 40 (PRAS40) (a repressor). In tumor cells, mTORC1 activity is aberrantly elevated. Diverse positive and negative growth signals influence the activity level of mTORC1, many of which converge upon the tuberous sclerosis complex 1 (TSC1)/TSC2 complex and Ras homolog enriched in brain (Rheb). PI3K receives activating signals from growth factor receptors or it may be activated constitutively in some tumors. Phosphatase and tensin homolog (PTEN) reverses the action of PI3K and functions as a tumor suppressor. Akt also promotes mTORC1 activity by phosphorylating TSC1/TSC2 and PRAS40, resulting in guanosine-5’-triphosphate (GTP) loading of Rheb and suppression of the PRAS40 repressor. Downstream, mTORC1 phosphorylates the 70-kDa ribosomal protein S6 kinase (p70S6K) (activation) and eukaryotic translation initiation factor 4E binding protein (4EBP-1) (inhibition of negative regulator) to increase messenger RNA translation of specific proteins. mTOR-regulated proteins include D-type cyclins and c-Myc (which increase cell proliferation), hypoxia-inducible factor-1α (HIF-1α) (which increases synthesis of the proangiogenic factor vascular endothelial growth factor [VEGF]), various glycolytic enzymes, and growth factors (which can promote cell survival). Activation and inhibition induced by direct phosphorylation at one or more sites is indicated by a phosphate (P). The mTOR inhibitors (rapamycin, temsirolimus, everolimus, deforolimus) inhibit mTORC1 by first binding to the intracellular protein FK506 binding protein 1A, 12 kDa (FKBP12); the resultant mTOR inhibitor-FKBP12 complex then binds mTOR, blocking mTORC1 to inhibit its kinase activity. Through the specific inhibition of mTORC1 activity, the mTOR inhibitors display a multifunctional biologic activity profile, blocking cell proliferation, cell growth, cell survival, and angiogenesis in preclinical tumor models. Figure reprinted with permission from Wyeth Pharmaceuticals, Collegeville, PA, USA.Abbreviations: MAPK, mitogen-activated protein kinase; S6RP, S6 ribosomal protein.

Publication

Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC). (2010) Rohan Shahani, et al. Drug Healthc Patient Saf. 2010;2:85-91. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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