(A) Stimuli such as insulin and IGF-1 activate PI3K/Akt pathway, resulting in the phosphorylation of PRAS40 and TSC2. Phosphorylation of both PRAS40 and TSC2 reverses their suppression on the activation of mTOR pathway, including the phosphorylation of mTOR's downstream factors, such as 4E-BP1 and S6K. mTORC1 also phosphorylates PRAS40. The phosphorylation of PRAS40 promotes IRS1 expression and phosphorylation in turn through a positive control mechanism. (B) Unphosphorylated PRAS40 and TSC2 repress mTORC1 signaling. (C) Under certain conditions, phosphorylated PRAS40 promotes the signaling of IR/PI3K/Akt pathway and mTOR pathway through increasing IR phosphorylation. PRAS40 could be either phosphorylated by PIM1, PKM2 and DYRK3. IGF-1, insulin-like growth factor-1; TSC2, tumor sclerosis complex 2; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; S6K, ribosomal protein S6 kinases; IR, insulin receptor; PIM1, Proviral integration site for Moloney murine leukemia virus-1; PKM2, Pyruvate kinase M2; DYRK3, The dual specificity tyrosine-phosphorylation-regulated kinase 3.