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c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by

Petia P Simeonova1, Shiyi Wang, Tracy Hulderman

  • 1TMBB, HELD, National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia 26505, USA. PSimeonova@cdc.gov

The Journal of Biological Chemistry
|November 28, 2001
PubMed

Insights

Arsenic exposure activates the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) pathway, a key regulator of cell growth. This activation, involving c-Src, may mediate arsenic-induced changes in the urinary tract lining.

Area of Science:

  • Environmental toxicology
  • Cancer research
  • Cell signaling

Background:

  • Arsenic exposure is linked to increased cancer risk, particularly in the skin, urinary bladder, and respiratory tract.
  • Arsenic acts as a tumor promoter by influencing cell proliferation pathways.
  • The epidermal growth factor receptor (EGFR)-extracellular signal-regulated protein kinase (ERK) pathway is crucial for regulating cellular growth.

Purpose of the Study:

  • To investigate the mechanism by which arsenic activates EGFR and ERK signaling in human uroepithelial cells.
  • To determine the role of c-Src in arsenic-induced EGFR and ERK activation.
  • To examine the in vivo relevance of these findings in a mouse model of arsenic exposure.

Main Methods:

  • In vitro studies using a human uroepithelial cell line exposed to arsenic.
  • Analysis of EGFR and ERK phosphorylation, and c-Src activity.
  • In vivo studies involving mice exposed to arsenic in drinking water.
  • Assessment of EGFR, ERK, and c-Src in mouse urinary bladders.

Main Results:

  • Arsenic activates EGFR and ERK in human uroepithelial cells in a ligand-independent manner.
  • Arsenic-induced EGFR activation does not involve the Tyr(1173) autophosphorylation site.
  • c-Src activity is induced by arsenic and is essential for EGFR and ERK activation.
  • In mice, arsenic exposure activates EGFR and ERK in the urinary bladder, increasing c-Src interaction with EGFR.

Conclusions:

  • Arsenic activates the EGFR-ERK pathway in urothelial cells via ligand-independent mechanisms involving c-Src.
  • These findings suggest a molecular pathway through which arsenic exposure can lead to phenotypic alterations in the uroepithelium.
  • The study provides insights into the mechanisms underlying arsenic-induced urothelial carcinogenesis.

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