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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4).

Authors: Sollome, James J; Thavathiru, Elangovan; Camenisch, Todd D; Vaillancourt, Richard R

Published In Cell Signal, (2014 Jan)

Abstract: Human MAP3K4 (MTK1) functions upstream of mitogen activated protein kinases (MAPKs). In this study we show MTK1 is required for human epidermal growth factor receptor 2/3 (HER2/HER3)-heregulin beta1 (HRG) induced cell migration in MCF-7 breast cancer cells. We demonstrate that HRG stimulation leads to association of MTK1 with activated HER3 in MCF-7 and T-47D breast cancer cells. Activated HER3 association with MTK1 is dependent on HER2 activation and is decreased by pre-treatment with the HER2 inhibitor, lapatinib. Moreover, we also identify the actin interacting region (AIR) on MTK1. Disruption of actin cytoskeletal polymerization with cytochalasin D inhibited HRG induced MTK1/HER3 association. Additionally, HRG stimulation leads to extracellular acidification that is independent of cellular proliferation. HRG induced extracellular acidification is significantly inhibited when MTK1 is knocked down in MCF-7 cells. Similarly, pre-treatment with lapatinib significantly decreased HRG induced extracellular acidification. Extracellular acidification is linked with cancer cell migration. We performed scratch assays that show HRG induced cell migration in MCF-7 cells. Knockdown of MTK1 significantly inhibited HRG induced cell migration. Furthermore, pre-treatment with lapatinib also significantly decreased cell migration. Cell migration is required for cancer cell metastasis, which is the major cause of cancer patient mortality. We identify MTK1 in the HER2/HER3-HRG mediated extracellular acidification and cell migration pathway in breast cancer cells.

PubMed ID: 24036211 Exiting the NIEHS site

MeSH Terms: Acids/metabolism*; Actin Cytoskeleton/drug effects; Actin Cytoskeleton/metabolism; Actins/metabolism; Amino Acid Sequence; Cell Movement*/drug effects; Extracellular Space/drug effects; Extracellular Space/metabolism*; Female; Gene Knockdown Techniques; Humans; Immunoprecipitation; MAP Kinase Kinase Kinase 4/chemistry; MAP Kinase Kinase Kinase 4/metabolism; MCF-7 Cells; Molecular Sequence Data; Molecular Weight; Neuregulin-1/pharmacology; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation/drug effects; Phosphotyrosine/metabolism; Protein Binding/drug effects; Protein Structure, Tertiary; Receptor, ErbB-2/metabolism*; Receptor, ErbB-3/metabolism*

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