Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K
Fig 1
PI3K → AKT1 signaling is regulated by multiple layers of negative feedback that fine-tune its control of growth, cell cycle commitment and survival.
(A) Feed-forward network of interactions from growth receptors to PI3K and AKT1 (detailed description of molecular mechanisms in Methods & Model). Box 1: AKT1 activates the mTORC1 pathway, driving volume growth; box 2: AKT1 blocks the GSK3β pathway responsible for dampening cell cycle entry and survival signaling; box 3: AKT1 blocks the FoxO transcription factors that drive expression of anti-proliferative and pro-apoptotic genes; box 4: AKT1 promotes cell survival by keeping the pro-apoptotic protein BAD in check. (B) The mTORC1 pathway feeds back to dampen PI3K → AKT1 signaling by mediating the degradation of insulin receptor substrates (red arrows), aiding the cytoplasmic translocation of PTEN (purple arrows) and dampening mTORC2 activation (orange arrows).