Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, Compound 5

Ziqiu Wang, Baochun Zhang, Meifang Wang, Brian I. Carr

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Extracellular signal-regulated kinase (ERK) plays a central role in regulating cell growth, differentiation, and apoptosis. We previously found that 2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone or Compound 5 (Cpd 5), is a Cdc25A protein phosphatase inhibitor and causes prolonged, strong ERK phosphorylation which is triggered by epidermal growth factor receptor (EGFR) activation. We now report that Cpd 5 can directly cause ERK phosphorylation by inhibiting Cdc25A activity independently of the EGFR pathway. We found that Cdc25A physically interacted with and de-phosphorylated phospho-ERK both in vitro and in cell culture. Inhibition of Cdc25A activity by Cpd 5 resulted in ERK hyperhosphorylation. Transfection of Hep3B human hepatoma cells with inactive Cdc25A mutant enhanced Cpd 5 action on ERK phosphorylation, whereas over-expression of Cdc25A attenuated this Cpd 5 action. Furthermore, endogenous Cdc25A knock-down by Cdc25A siRNA resulted in a constitutive-like ERK phosphorylation and Cpd 5 treatment further enhanced it. In EGFR-devoid NR6 fibroblasts and MEK (ERK kinase) mutated MCF7 cells, Cpd 5 treatment also resulted in ERK phosphorylation, providing support for the idea that Cpd 5 can directly act on ERK phosphorylation by inhibiting Cdc25A activity. These data suggest that phospho-ERK is likely another Cdc25A substrate, and Cpd 5-caused ERK phosphorylation is probably regulated by both EGFR-dependent and EGFR-independent pathways.

Original languageEnglish
Pages (from-to)437-444
Number of pages8
JournalJournal of Cellular Physiology
Volume204
Issue number2
DOIs
Publication statusPublished - Aug 2005

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Phosphoprotein Phosphatases
Extracellular Signal-Regulated MAP Kinases
Epidermal Growth Factor Receptor
Phosphorylation
Chemical activation
Mitogen-Activated Protein Kinase 7
cdc25 Phosphatases
Mercaptoethanol
Mitogen-Activated Protein Kinase Kinases
MCF-7 Cells
Cell growth
Fibroblasts
Cell culture
Small Interfering RNA
Transfection
Cell Differentiation
Hepatocellular Carcinoma
Phosphotransferases
Cell Culture Techniques
Apoptosis

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Cdc25A and ERK interaction : EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, Compound 5. / Wang, Ziqiu; Zhang, Baochun; Wang, Meifang; Carr, Brian I.

In: Journal of Cellular Physiology, Vol. 204, No. 2, 08.2005, p. 437-444.

Research output: Contribution to journalArticle

Wang, Ziqiu ; Zhang, Baochun ; Wang, Meifang ; Carr, Brian I. / Cdc25A and ERK interaction : EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, Compound 5. In: Journal of Cellular Physiology. 2005 ; Vol. 204, No. 2. pp. 437-444.
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