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

ABSTRACT: 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 MAPK, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, the first three members of HER family (HER1-3) can form homo- and hetero-dimers, and there is considerable evidence suggesting that the receptor dimers differentially activate intracellular signaling pathways. To better understand the interactions in this system, we pursued multi-factorial experiments where HER dimerization patterns and signaling pathways were rationally perturbed. We measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38 MAPK, 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. We hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated this hypothesis using a combination of model-based analysis to quantify the HER dimerization patterns, and by clustering the activation data in multiple ways to confirm that the HER receptor dimer is a better predictor of the signaling through p38 MAPK, ERK and AKT pathways than the total HER receptor expression and activation levels. We then pursued combinatorial inhibition studies to identify the causal regulatory interactions between sentinel signaling proteins. Quantitative analysis of the collected data using the modular response analysis (MRA) and its Bayesian Variable Selection Algorithm (BVSA) version allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways in HME cells. Results of the BVSA/MRA and cluster analysis were in agreement with each other.

SUBMITTER: Gong C

PROVIDER: S-EPMC4540226 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Gong Chunhong C Zhang Yi Y Shankaran Harish H Resat Haluk H

Molecular bioSystems 20141015 1

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 MAPK, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, the first three members of HER family (HER1-3) can form homo- and hetero-dimers, and there is considerable evidence suggesting that the receptor dimers differentially activate intracellular sig ...[more]

PMID: 25315124

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Project description:BackgroundMembers of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression.MethodsGene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA-mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression.Results775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3), autocrine growth factor signalling (VEGF, PDGF) and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN), linking them to the hyper-poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2-dependent transformation through suppressed IGF1 signalling. We show that IGF1-dependent signalling and proliferation were enhanced in ErbB2-overexpressing cells, whilst loss of ErbB2 expression by siRNA silencing reduced IGF1 signalling. Furthermore, IGFBP3 knockdown resulted in basal ERK and Akt activation in luminal epithelial cells and increased invasiveness and anchorage-independent colony formation in SKBR3 cells.ConclusionsThese data show IGFBP3 as a negative regulator of transformation and that its down-regulation enhances IGF1-dependent signalling. They also show that ErbB2 can up-regulate IGF1-dependent signalling, possibly via the regulated expression of IGFBP3.

Dataset Information

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

Publications

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

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