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Updated: Mar 9, 2026

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
08:40

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline

Published on: November 29, 2016

10.9K

Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK

Andrew M Kidger1, Linda K Rushworth1, Julia Stellzig1

  • 1Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|January 6, 2017
PubMed

Insights

Dual-specificity MAP kinase phosphatases (MKPs/DUSPs), like DUSP5, normally limit extracellular signal-regulated kinase (ERK) signaling. This study reveals DUSP5 paradoxically enhances cytoplasmic ERK activity, impacting cancer cell proliferation and transformation.

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Molecular mechanisms of cancer

Background:

  • Extracellular signal-regulated kinase (ERK) signaling is crucial for cell growth and is tightly regulated by feedback mechanisms.
  • Dual-specificity MAP kinase phosphatases (MKPs/DUSPs) are key negative regulators of ERK signaling, but their precise interactions with other feedback loops are not fully understood.

Purpose of the Study:

  • To elucidate the complex interactions between DUSP5 and other feedback mechanisms within the ERK signaling pathway.
  • To investigate the role of DUSP5 in regulating ERK activity in the context of oncogenic mutations, specifically BRAFV600E.

Main Methods:

  • Investigated the subcellular localization and enzymatic activity of DUSP5 in relation to ERK.
  • Utilized genetic manipulation (DUSP5 deletion) and expression of oncogenic BRAFV600E to study feedback loop dynamics.
  • Assessed the impact of these manipulations on ERK signaling, cell proliferation, and cell fate.

Main Results:

  • DUSP5 anchors and inactivates ERK in the nucleus but paradoxically increases and prolongs cytoplasmic ERK activity by relieving RAF inhibition.
  • Expression of oncogenic BRAFV600E reprograms DUSP5 into a cell-wide ERK inhibitor, promoting proliferation and transformation.
  • DUSP5 deletion leads to BRAFV600E-induced ERK hyperactivation and cellular senescence.

Conclusions:

  • Feedback interactions within the ERK pathway are critical for controlling cell proliferation and transformation.
  • DUSP5 plays an oncogene-specific role in modulating ERK signaling and cell fate, highlighting its complex regulatory function.
Keywords:
DUSPERKMAPKMKPsignaling

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