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Heterogeneous kinetics of AKT signaling in individual cells are accounted for by variable protein concentration

Abstract:

In most solid cancers, cells harboring oncogenic mutations represent only a sub-fraction of the entire population. Within this sub-fraction the expression level of mutated proteins can vary significantly due to cellular variability limiting the efficiency of targeted therapy. To address the causes of the heterogeneity, we performed a systematic analysis of one of the most frequently mutated pathways in cancer cells, the phosphatidylinositol 3 kinase (PI3K) signaling pathway. Among others PI3K signaling is activated by the hepatocyte growth factor (HGF) that regulates proliferation of hepatocytes during liver regeneration but also fosters tumor cell proliferation. HGF-mediated responses of PI3K signaling were monitored both at the single cell and cell population level in primary mouse hepatocytes and in the hepatoma cell line Hepa1_6. Interestingly, we observed that the HGF-mediated AKT responses at the level of individual cells is rather heterogeneous. However, the overall average behavior of the single cells strongly resembled the dynamics of AKT activation determined at the cell population level. To gain insights into the molecular cause for the observed heterogeneous behavior of individual cells, we employed dynamic mathematical modeling in a stochastic framework. Our analysis demonstrated that intrinsic noise was not sufficient to explain the observed kinetic behavior, but rather the importance of extrinsic noise has to be considered. Thus, distinct from gene expression in the examined signaling pathway fluctuations of the reaction rates has only a minor impact whereas variability in the concentration of the various signaling components even in a clonal cell population is a key determinant for the kinetic behavior.

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Front Physiol
Front Physiol 3: 451
28th Nov 2012

René Meyer, Lorenza A D'Alessandro, Sandip Kar, Bernhard Kramer, Bin She, Daniel Kaschek, Bettina Hahn, David Wrangborg, Johan Karlsson, Mats Kvarnström, Mats Jirstrand, Wolf-Dieter Lehmann, Jens Timmer, Thomas Höfer, Ursula Klingmüller

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[René Meyer] [Lorenza D'Alessandro] [Daniel Kaschek] [Jens Timmer] [Ursula Klingmüller]

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  • Created: 10th Jan 2013 at 14:27
  • Last updated: 24th Oct 2013 at 16:15

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