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Kinase suppressor of Ras inhibits the activation of extracellular ligand-regulated (ERK) mitogen-activated protein

T Joneson1, J A Fulton, D J Volle

  • 1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.

The Journal of Biological Chemistry
|April 29, 1998
PubMed

Insights

Kinase suppressor of Ras (KSR) acts as a negative regulator of Ras signaling. Ectopic KSR expression inhibits extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAP) activation, impacting cell growth and development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Kinase suppressor of Ras (KSR) is a loss-of-function allele involved in Ras signaling pathways.
  • KSR is suggested to be a positive regulator functioning between Ras and Raf or in a parallel pathway.

Purpose of the Study:

  • To investigate the effect of mammalian KSR on extracellular ligand-regulated (ERK) mitogen-activated protein (MAP) kinase activation in fibroblasts.
  • To determine the role of the KSR kinase domain in modulating ERK MAP kinase activity.

Main Methods:

  • Ectopic expression of KSR and its deletion mutants in fibroblasts.
  • Assessing ERK MAP kinase activation in response to various stimuli (insulin, phorbol ester, activated Ras/Raf).
  • Evaluating the effect of KSR on RasVal-12-induced cell transformation and membrane ruffling.

Main Results:

  • Ectopic KSR expression inhibited ERK MAP kinase activation induced by insulin, phorbol ester, and activated Ras/Raf.
  • The KSR kinase domain was found to be necessary and sufficient for this inhibitory effect.
  • KSR inhibited RasVal-12-induced cell transformation but did not affect membrane ruffling.

Conclusions:

  • Mammalian KSR acts as a potent inhibitor of ERK MAP kinase signaling.
  • KSR modulates a critical pathway for normal and oncogenic cell growth and development.
  • These findings suggest KSR's role as a negative regulator in specific contexts of Ras signaling.

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