Computational modeling of cell signaling dynamics: Overcoming the tyranny of the receptor
Monday, April 18, 2016
3:00 pm - 4:00 pm
Gross Hall 330
Lisa Tucker-Kellogg, Duke-NUS Medical School in Cancer & Stem Cell Biology (CSCB) and in the Centre for Computational Biology (CCB)
In the information processing of a cell, external chemical stimuli (e.g., hormones or cytokines) are communicated to intracellular systems through biochemical reaction networks that can be viewed as systems of ordinary differential equations (ODEs) representing changes in concentration over time. Well-studied pathways such as PI3K-Akt, TGFb-Smad, and TRAIL-induced apoptosis have extensive published evidence and accepted enzymatic reactions, which can be used for building such models. Unfortunately, models rarely match reality. In this work, we view discrepancies between models and reality as starting points for identifying gaps in accepted understanding, and for guiding experiments to delineate novel effects. We present three case studies: (1) In TGF-¿1 signaling, the long-term decline of phospho-Smad suggested novel regulation of the PPM1A phosphatase in HaCaT cells. (2) In Akt signalling, a discrepancy between PIP3 dynamics and phospho-Akt in serum stimulated fibroblasts pointed to a novel effect that regulates the membrane translocation of Akt. (3) In TRAIL-induced apoptosis, an anti-cancer drug (LY30) caused caspase-8 activity to increase but with an unexpected delay, which pointed to a non-monotonic effect of LY30 on the apoptosis inhibitor c-FLIP.