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Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling

Seung-Keun Hong1, Seunghee Yoon, Cas Moelling

  • 1Department of Biochemistry, The Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.

The Journal of Biological Chemistry
|October 7, 2009
PubMed

Insights

Extracellular signal-regulated kinases (ERK1/2) have a noncatalytic function in cell signaling. This study reveals ERK1/2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitogen-activated protein kinases (MAPKs), including ERK1/2, are crucial regulators of cellular processes.
  • Kinase activity is considered the primary function of ERK1/2 in signal transduction.
  • The role of noncatalytic functions of ERK1/2 in cellular signaling remains less understood.

Purpose of the Study:

  • To investigate the potential noncatalytic functions of ERK1/2 in signal transduction.
  • To elucidate the specific roles of ERK1/2 kinase activity versus noncatalytic functions in mediating growth arrest and cell cycle regulation.
  • To explore the involvement of ERK1/2 in cell type-specific responses.

Main Methods:

  • Utilized RNA interference to ablate ERK1/2 expression in human tumor cell lines (LNCaP, U251, TT).
  • Employed active site-disabled ERK mutants (ERK1-K71R, ERK2-K52R, ERK2-D147A) to competitively inhibit endogenous ERK1/2.
  • Generated stable cell lines with knocked-down ERK1/2 and introduced kinase-deficient rat-derived ERK mutants (ERK2-K52R, ERK2-T183A/Y185F) for rescue experiments.

Main Results:

  • Sustained activation of the Raf/MEK/ERK pathway induced growth arrest and altered cell cycle regulators, effects abrogated by ERK1/2 ablation.
  • Active site-disabled ERK mutants failed to block Raf/MEK-induced growth arrest and cell cycle changes, despite inhibiting downstream phosphorylation events.
  • Kinase-deficient ERK2-K52R selectively restored growth inhibitory signaling in ERK1/2-depleted cells, indicating a noncatalytic function.
  • ERK2-T183A/Y185F mutant was less effective, suggesting the importance of TEY site phosphorylation for some functions.

Conclusions:

  • ERK1/2 plays a significant role in mediating growth arrest and cell cycle regulation through functions beyond its canonical kinase activity.
  • Noncatalytic functions of ERK1/2 are critical for specific aspects of signal transduction, including growth inhibition.
  • The findings expand the understanding of ERK1/2 signaling pathways and their involvement in cancer biology.

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