Overview of essential intracellular members of the mTORC1-pathway and respective targeted therapies.

<p>Signaling from growth factor receptors such as EGFR or a nutrient rich environment leads to an activation of the mTOR-pathway, while nutrient depletion inhibits signaling. The mTORC1-complex consists of the mTOR-protein itself and the subunits raptor (regulatory associated protein of mTOR), mLST8 (mammalian lethal with sec thirteen 8) and PRAS40 (proline-rich Akt1 substrate 1). Activation of the pathway leads to phosphorylation of the ribosomal protein S6 at phospho-sites Ser235/236 and Ser240/244 by the S6-kinase (S6K). Additionally, the translational repressor 4EBP1 (eukaryotic initiation factor 4E binding protein-1) is phosporylated at Thr37/Thr46, thereby relieving its translational inhibition and promoting translation especially of mRNAs with a TOP motif [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127123#pone.0127123.ref014" target="_blank">14</a>]. First generation mTORC1-inhibitors are rapamycin and its derivatives temsirolimus and everolimus. Mechanistically these compounds bind the intracellular adaptor protein FKBP12 to form an allosteric mTORC1 inhibitory complex. 4EBP1 phosphorylation though mTORC1-dependent is largely resistant to the mTORC1 inhibitor rapamycin and its derivatives. Recently, ATP-competitive mTORC (2^nd generation) inhibitors like torin1 and torin2 which are efficient in dephosphorylating 4EBP1 have been developed [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127123#pone.0127123.ref015" target="_blank">15</a>].