Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells

Gong, Chunhong; Zhang, Yi; Shankaran, Harish; Resat, Haluk

doi:10.1039/c4mb00471j

Title: Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells

Journal Article · Thu Oct 02 00:00:00 EDT 2014 · Molecular BioSystems

DOI:https://doi.org/10.1039/c4mb00471j· OSTI ID:1184915

Gong, Chunhong ^[1]; Zhang, Yi ^[1]; Shankaran, Harish ^[1]; Resat, Haluk ^[2]

Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computational Biology and Bioinformatics Group
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computational Biology and Bioinformatics Group; Washington State Univ., Pullman, WA (United States). School of Chemical Engineering and Bioengineering; Washington State Univ., Pullman, WA (United States). School of Electrical Engineering and Computer Science

Human epidermal growth factor receptors (HER, also known as ErbB) drive cellular proliferation, pro-survival and stress responses by activating several downstream kinases, in particular ERK, p38, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, first three members of HER family (HER1-3) can form homo- and hetero-dimers. Based on the considerable evidence which suggest that every receptor dimer activates intracellular signaling pathways differentially, we hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated our hypothesis using a combination of model-based analysis to quantify the HER dimerization patterns and multi-factorial experiments where HER dimerization patterns and signaling crosstalk were rationally perturbed. We have measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38, JNK, STAT3 as a function of time in a panel of human mammary epithelial (HME) cells expressing different levels of HER1-3 stimulated with various ligand combinations. Our analysis using multiple ways of clustering the activation data has confirmed that the HER receptor dimer is a better predictor of the signaling through p38, ERK and AKT pathways than the total HER receptor expression and activation levels. Targeted inhibition studies to identify the causal effects allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC05-76RL01830; AC06-76RL01830; 5R01GM072821-07

OSTI ID:: 1184915

Report Number(s):: PNNL-SA-100045; MBOIBW; 400412000

Journal Information:: Molecular BioSystems, Vol. 11, Issue 1; ISSN 1742-206X

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 11 works

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