Review Volume 3, Issue 3 pp 192—222

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

Figure 3. Interactions between the Ras/Raf/MEK/ERK, Ras/PI3K/PTEN/mTOR and Wnt/β-Catenin Pathways that Result in the Regulation of Protein Translation and Gene Transcription. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways can affect protein translation by complex interactions regulating the mTORC1 (grouped together in a purple box) and mTORC2 (grouped together in a blue box) complexes. GF stimulation results in GFR activation which can activate both the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways. Akt can phosphorylate and inhibit the effects of GSK-3β, TSC2 and PRAS-40 (indicated in red ovals), which result in mTORC1 activation. ERK and PDK1 can phosphorylate p90Rsk1 (indicated in green ovals), which in turn can phosphorylate and inhibit TSC2 (indicated in red oval). Akt-mediated phosphorylation of GSK-3β also affects the Wnt/β-catenin pathway and EMT. Rapamycin targets mTORC1 and inhibits its activity and also results in inhibition of downstream p70S6K. The effects of rapamycin are complex as long term administration of rapamycin may prevent mTOR from associating with mTORC2 and hence full activation of Akt is prevented. However, rapamycin treatment may result in activation of PI3K, by inhibiting the effects of p70S6K on IRS-1 phosphorylation which results in PI3K and Akt activation. Also rapamycin treatment may result in the activation of ERK in some cells, presumably by inhibition of the p70S6K mediated inhibition of IRS1. These later two effects of rapamycin could have positive effects on cell growth. Energy deprivation will result in the activation of serine/threonine kinase 11 (STK11 a.k.a LKB1) and AMPkinase (AMPK) which can result in TSC2 activation (indicated in red ovals) and subsequent suppression of mTORC1. In contrast Akt can phosphorylate and inhibit the activity of AMPK. Inhibition of PDK-1 activity can also result in activation of mTORC1, presumably by suppression of p70S6K and hence inhibition of IRS1 (indicated in red oval) effects on PI3K activity. The PTEN, TSC1, TSC2 and LKB1 tumor suppressor genes all converge on the mTORC1 complex to regulate protein translation. Thus the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways can finely tune protein translation and cell growth by regulating mTORC1. Rapamycin can have diverse effects on these processes. Also these pathways can interact with the Wnt/β-catenin pathway which is important in developmental processes, EMT and CICs. Upon activation of the Wnt pathway, β-catenin forms a complex with Bcl-9, PYGO, plakoglobulin and TCF/LEF which result in the transcription of critical genes including cyclin D1, c-Myc, SALL4 and PPARδ.