Heterogeneous kinetics of AKT signaling in individual cells are accounted for by variable protein concentration
Artikel i vetenskaplig tidskrift, 2012

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.

AKT

mathematical modeling

single cell heterogeneity

live cell imaging

PI3 kinase

HGF

hepatocellular carcinoma

primary hepatocytes

Författare

René Meyer

Lorenza A. D'Alessandro

Sandip Kar

Bernhard Kramer

Bin She

Daniel Kaschek

Bettina Hahn

David Wrangborg

Mats Kvarnström

Wolf-Dieter Lehmann

Jens Timmer

Thomas Höfer

Ursula Klingmüller

Frontiers in Physiology

1664-042X (ISSN)

Vol. 3 451

Ämneskategorier

Beräkningsmatematik

Bioinformatik och systembiologi

Signalbehandling

Fundament

Grundläggande vetenskaper

Drivkrafter

Innovation och entreprenörskap

Styrkeområden

Livsvetenskaper och teknik

DOI

10.3389/fphys.2012.00451