Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K
Fig 9
Summary of the molecular mechanisms that link PI3K hyperactivity to attenuated Plk1 expression and failure of cytokinesis.
(A) Degradation and re-synthesis of the PI3K subunit p110 is driven by PLCĪ³-dependent activation of the NEDDL4 (red links) and FoxO3 (orange link), respectively. During G2, loss of strong PI3K / AKT1 signaling is required for nuclear translocation of FoxO3 and/or FoxO1, which aids Plk1 accumulation to levels that can outlast its degradation in anaphase (modeled via the Plk1H node). During telophase this remaining pool of Plk1 localizes to the central spindle and promotes the assembly of a contractile ring by recruiting the RhoA GEF Ect2. Red nodes: key pathway linking PI3K and AKT1 dynamics to Plk1 and cytokinesis. (B) Plk1 inhibition at different points along the cell cycle leads to four distinct failure modes. Image credits: https://commons.wikimedia.org/wiki/File:Mitosis_cells_ sequence.svg.