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

James J. Sollome, Elangovan Thavathiru, Todd D Camenisch, Richard Vaillancourt

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)70-82
Number of pages13
JournalCellular Signalling
Volume26
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Cell Movement
MCF-7 Cells
Breast Neoplasms
Actins
heregulin beta1
Cytochalasin D
Neoplasms
Mitogen-Activated Protein Kinases
Polymerization
Therapeutics
Cell Proliferation
Neoplasm Metastasis
Mortality
lapatinib

Keywords

  • HER2
  • HER3
  • MEKK4
  • Migration
  • MTK1

ASJC Scopus subject areas

  • Cell Biology

Cite this

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4). / Sollome, James J.; Thavathiru, Elangovan; Camenisch, Todd D; Vaillancourt, Richard.

In: Cellular Signalling, Vol. 26, No. 1, 01.2014, p. 70-82.

Research output: Contribution to journalArticle

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