Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K
Fig 2
Two hypothesized negative feedback loops control degradation and re-synthesis of PI3K and AKT1 signaling.
(A) Degradation of the PI3K subunit p110 may be driven by the PLCγ-dependent activation of the NEDDL4 ubiquitin ligase (red links); re-synthesis of p110 may be driven by FoxO3, which re-enters the nucleus following p110 degradation, as AKT1 activity falls (orange link). (B) Growth Signaling Module of our Boolean model, including the degradation/re-synthesis circuit in control of p110 expression (left, dark green), basal PI3K/AKT1 signaling (middle), downstream effectors of AKT1 (mTORC1 signaling, GSK3 & FoxO1, bottom), and the MAPK cascade (right). Black →: activation; red ⊣: inhibition; thick red links: p110 degradation; thick orange loop: p110 re-synthesis. (C) Periphery: sequence of network states along the synchronous limit cycle of the core PI3K circuit. Orange/blue borders: ON (expressed and/or active) / OFF (not expressed and/or inactive) node. Middle: state transition graph of the general asynchronous model (one random node updated per timestep; sampled for 10,000 steps), yielding a complex limit cycle that follows the synchronous cycle. Node size: visitation frequency; label: most similar synchronous cycle state; node color: overlap of similar synchronous cycle state (one minus normalized Hamming distance); layout: Kamada-Kawai algorithm (NetworkX [67], Python). (D) Overlap of states along a general asynchronous update trajectory (y axis) with each attractor state along the synchronous limit cycle (x axis). Time-step: update of a single random node.