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 2. Overview of the Ras/PI3K/PTEN/Akt/mTOR Pathway and Potential Sites of Therapeutic Intervention. The Ras/PI3K/PTEN/mTOR pathway is regulated by Ras (indicted in green ovals), as well as various upstream growth factor receptors (indicated in purple). Sites where various small molecule inhibitors suppress this pathway are indicated by red octagons. Naturally occurring miRNAs have been discovered to certain components of this pathway (e.g., PTEN) and are indicated in a red triangle; other miRNAs to other components, especially tumor suppressor genes will likely be discovered. The downstream transcription factors regulated by this pathway are indicated in diamond shaped purple (active) or red (inactivated) outlines. This drawing depicts some of the complicated regulations of this pathway by both positive and negative phosphorylation events which serve to fine tune this pathway. Phosphorylation of some molecules by certain kinases (e.g., phosphorylation of β-catenin by glycogen synthase kinase-3β [GSK-3β], indicated in red oval) results in their proteosomal degradation (indicated in red box), while phosphorylation of some molecules by certain kinases (e.g., β-catenin by Akt) results in their activation (nuclear translocation, indicated in green box). The Ras/PI3K/PTEN/Akt/mTOR pathway plays a key role in regulating p53 activity (indicated in purple diamond) by phosphorylating MDM2 (indicated in red oval) which controls the stability of p53 by ubiquitination. The Ras/PI3K/PTEN/Akt/mTOR pathway plays a key role in regulating critical proteins involved in protein translation (indicated in green ovals), especially those necessary for the translation of “weak” mRNAs (mTORC1, grouped together a purple box). This pathway also indicates that Akt can result in the activation of downstream mTOR which can subsequently serve as either a negative feed back to inactivate Akt by p70S6K or activate Akt by mTORC2 (grouped together in a blue box). GF = growth factor, GFR = growth factor receptor.