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ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome

Yun-Wei Lin1, Show-Mei Chuang, Jia-Ling Yang

  • 1Molecular Carcinogenesis Laboratory, Institute of Biotechnology, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China.

The Journal of Biological Chemistry
|April 5, 2003
PubMed

Insights

Lead (Pb(II)) exposure sustains extracellular signal-regulated kinase 1/2 (ERK1/2) activation in lung cancer by degrading mitogen-activated protein kinase phosphatase 1 (MKP-1) via the ubiquitin-proteasome pathway, promoting cancer cell survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Toxicology

Background:

  • Sustained extracellular signal-regulated kinase 1/2 (ERK1/2) activation is crucial in cancer, but its regulation beyond the Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) pathway is not fully understood.
  • Lead (Pb(II)), a known carcinogen, induces persistent ERK1/2 activity in human lung cancer cells, suggesting mechanisms beyond canonical signaling.

Purpose of the Study:

  • To elucidate the novel mechanism underlying sustained ERK1/2 activation induced by Pb(II) in human lung cancer cells.
  • To investigate the role of mitogen-activated protein kinase phosphatase 1 (MKP-1) in Pb(II)-mediated ERK1/2 signaling.

Main Methods:

  • Treatment of CL3 human lung cancer cells with Pb(II).
  • Analysis of ERK1/2 and MKP-1 protein and mRNA levels.
  • Assessment of MKP-1 ubiquitination and degradation using proteasome inhibitors and Western blotting.
  • Pharmacological inhibition of ERK1/2 activation and MKK1/2 constitutive activation experiments.
  • Evaluation of MKP-1 expression effects on ERK1/2 activity, c-Fos levels, and cytotoxicity.

Main Results:

  • Pb(II) treatment reduced MKP-1 protein levels, correlating with sustained ERK1/2 activation, despite inducing MKP-1 mRNA and protein synthesis.
  • MKP-1 underwent polyubiquitination and proteasomal degradation in Pb(II)-treated cells; this was attenuated by proteasome inhibitors and ERK1/2 inhibition.
  • Constitutive MKK1/2 activation also triggered MKP-1 ubiquitination and degradation in various cell lines.
  • Functional MKP-1 expression counteracted Pb(II)-induced ERK1/2 activation, reduced c-Fos levels, and enhanced cytotoxicity.

Conclusions:

  • Activated ERK1/2 promotes its own sustained activation by inducing MKP-1 degradation through the ubiquitin-proteasome pathway.
  • This feedback loop, involving Pb(II)-induced MKP-1 degradation, facilitates prolonged ERK1/2 signaling, potentially contributing to cancer cell survival and progression.
  • Targeting MKP-1 degradation could represent a therapeutic strategy against cancers associated with aberrant ERK1/2 activation.

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