Figure 8. Schematic of the PTEN/PI3K/Akt/mTOR axis in fibroblasts proposed in this manuscript.

mTOR, in complex with rictor and gβL, phosphorylates Akt on S⁴⁷³. Akt is subsequently phosphorylated on T³⁰⁸ by the actions of PDK1 downstream of PI3K. PTEN negatively regulates this activity. Akt directly phosphorylates and activates SF2/ASF to enhance EDA splicing and, through a series of steps involving the tuberous sclerosis complex and Rheb (depicted as the broken arrow), promotes mTOR/raptor/gβL activity. mTOR/raptor/gβL activates p70^S6K, which promotes FN protein translation as well as inhibiting insulin receptor substrate-1 (IRS-1) thereby inhibiting PI3K activity. In the absence of PTEN, high basal Akt activity results in augmented EDA splicing and p70^S6K-mediated FN expression. The FN expression is blocked by rapamycin. In cells with normal PTEN expression, PI3K activity is more sensitive to IRS-1 regulation and rapamycin in this case augments PI3K/Akt activity.