Epidermal growth factor and transforming growth factor-β1 enhance HK-2 cell migration through a synergistic increase of matrix metalloproteinase and sustained activation of ERK signaling pathway

Ya Chung Tian, Yung Chang Chen, Chiz Tzung Chang, Cheng Chieh Hung, Mai Szu Wu, Aled Phillips, Chih Wei Yang

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Epidermal growth factor (EGF) and transforming growth factor-β1 (TGF-β1), upregulated in renal diseases, have a combinational effect on epithelial-mesenchymal transformation (EMT) of renal proximal tubular cells. The aim of this study was to examine the mechanism regarding the combinational effect of EGF and TGF-β1 on cell migration following EMT. The results demonstrated that EGF (10 ng/ml) and TGF-β1 (3 ng/ml) synergistically increased cell migration, accompanied by an increase in matrix metalloproteinase-9 (MMP-9) gene expression, production and activity. Inhibition of MMP-9 production and activity by an MMP-2/MMP-9-specific inhibitor blocked the synergistic effect of EGF and TGF-β1 on cell migration. The kinetic profile of extracellular signal-regulated kinase (ERK) signals demonstrated that ERK1/2 activation was rapidly and strongly induced by EGF but delayed and less marked by TGF-β1 stimulation. In contrast, co-administration of EGF and TGF-β1 caused an early pronounced and persistent ERK1/2 activation. Inhibition of the ERK1/2 activity by PD98059 abrogated the synergistic effect of EGF and TGF-β1 on cell migration, MMP-9 production and activity, indicating that EGF and TGF-β1 converged at the ERK signaling pathway to mediate cell migration. This study demonstrates that EGF and TGF-β1 synergistically stimulate proximal tubular cell migration through the increased MMP-9 function and enhanced ERK1/2 activation.

Original languageEnglish
Pages (from-to)2367-2377
Number of pages11
JournalExperimental Cell Research
Issue number11
Publication statusPublished - Jul 1 2007
Externally publishedYes



  • Cell migration
  • Epidermal growth factor
  • Extracellular signal-regulated kinase
  • Matrix metalloproteinase
  • Transforming growth factor

ASJC Scopus subject areas

  • Cell Biology

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