Figure 1.

mTOR Signaling Cascade. mTOR regulates a number of key cellular processes in mammalian cells, including protein translation. mTOR can bind to GβL, Mlst8, PRAS40, and RAPTOR, forming the MTI sensitive complex, mTORC1.(Bhaskar and Hay 2007) In comparison, the components of mTORC2 include mTOR, GβL, mSIN1, RICTOR, and PROTOR/PRR5.(Bhaskar and Hay 2007) mTORC2, in concert with PDK1, activates AKT by phosphorylation. Activation of growth factor receptors, including IL-7R, IGF-1R, c-kit, and flt-3, via insulin, hormones, and growth factors, leads to activation of IRS-1. The activation of IRS-1 in turn leads to PI3K up-regulation. PI3K can also be activated by directly associating with the growth factor receptor at the cell membrane. Activated PI3K generates PIP₃ which can recruit AKT to the cell membrane so that PDK1 and TORC2 can activate it.(Wullschleger, et al 2006) The tumor suppressor PTEN negatively regulates PI3K by dephosphorylating its second messengers, i.e. PIP₃.(Mills, et al 2001) Inactivating mutations of PTEN, which are found in many tumor types, leads to excess activation of AKT, mTOR, p70S6 kinase 1 (S6K1) and can increase sensitivity to mTOR inhibition.(Neshat, et al 2001) Activated AKT then can phosphorylate TSC2, resulting in the inactivation of the TSC1:TSC2 complex, allowing for RHEB to activate mTORC1.(Wullschleger, et al 2006) The main downstream targets of activated mTORC1 are S6K1 and the inhibitor of cap-dependent translation, 4E-BP-1.(Wullschleger, et al 2006) The mTORC1 kinase phosphorylates S6K1. Phosphorylated- S6K1 induces TOP-translation and ribosomal biosynthesis as well as blocks apoptosis by phosphorylating the pro-apoptotic molecule BAD. In addition, P-S6K1 acts as a negative feedback mechanism for the mTOR pathway by down-regulating IRS-1.(Harrington, et al 2005) mTORC1 regulates cap-dependent protein translation via phosphorylation of 4E-BP-1.(Huang, et al 2003) When hypophosphorylated, 4E-BP1 binds tightly to eIF-4E, blocking the association of eIF-4E with eIF-4G. This blocks the formation of the eIF-4F translation initiation complex which is necessary for cap-dependent translation. When 4E-BP1 is phosphorylated by mTORC1, it is released from eIF4E, thereby facilitating translational initiation of mRNAs for a number of key intracellular proteins, including c-MYC, cyclin D1, and ornithine decarboxylase.(Faivre, et al 2006). Cyclin D1 forms a complex with CDK4 (cyclin dependent kinase 4) which is required for activation via phosphorylation of Rb (retinoblastoma protein).(Ewen, et al 1993) mTOR also facilitates the elimination of the cyclin dependent kinase inhibitor p27kip1 through interactions with p34cdc2, allowing cell cycle progression under the regulation of cyclin-dependent kinases, including cyclin-A.(Faivre, et al 2006) Arrows represent activation; Lines with circles represent inhibition. mTOR = mammalian target of rapamycin; PI3K = phosphoinositide 3-kinase; IRS = insulin receptor substrates; PTEN = phosphatase and tensin homologue deleted on chromosome ten; TSC = tuberous sclerosis; Rheb = ras homologue enriched in brain; p34^cdc2 = cyclin-dependent controlling kinase p34; p27^kip1 = cyclin-dependent kinase inhibitor kip1; cdks = cyclin-dependent kinases; pRb = retinoblastoma protein; S6 = ribosomal protein S6; 4E-BP1: eIF-4E binding protein; eIF = eukaryotic initiation factors; GβL = G protein beta subunit-like; mTORC = mTOR complex; PIP2 = phosphatidylinositol bisphosphate; PIP3 = phosphatidylinositol triphosphate; PDK1 = pyruvate dehydrogenase kinase, isozyme 1; Mlst8 = mammalian lethal with sec-13; PRAS40 = proline-Rich Akt substrate of 40kDa; mSIN1 = mammalian stress-activated protein kinase-interaction protein 1; and, PROTOR/PRR5 = Protein observed with Rictor-1/Proline-rich protein 5; GF = growth factor. Colour schematic: Yellow = mTOR; grey = Other proteins that bind to mTOR to form mTORC1/2; orange = targets phosphorylated by mTOR; pink = other down-stream-effectors; green = up-stream signaling molecules; purple = growth factor and receptor; red = drug.