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Insider information: how palmitoylation of Ras makes it a signaling double agent

Luc G Berthiaume1

  • 1Department of Cell Biology, MSB-555, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. luc.berthiaume@ualberta.ca

Science'S STKE : Signal Transduction Knowledge Environment
|October 3, 2002
PubMed

Insights

Ras GTPases regulate cell growth and survival, with mutations found in many cancers. This study shows Ras localization within cells, like the Golgi, influences distinct downstream signaling pathways, impacting cancer development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Ras small GTPases are key regulators of cell growth, differentiation, and survival.
  • Mutations in Ras are implicated in approximately 30% of human cancers.
  • Ras proteins are found on intracellular membranes due to posttranslational modifications.

Purpose of the Study:

  • To investigate the role of subcellular localization in Ras signaling.
  • To differentiate the activation kinetics and downstream effects of Ras at different cellular compartments.
  • To explore how Golgi-associated Ras activation influences specific signaling pathways.

Main Methods:

  • Utilized a novel fluorescent probe (GFP-Raf-1-RBS) to monitor GTP-bound Ras in live cells.
  • Compared H-Ras activation kinetics at the plasma membrane versus the Golgi apparatus.
  • Investigated downstream pathway activation (ERK, Akt, JNK) using oncogenic H-Ras chimeras tethered to the endoplasmic reticulum and Golgi.

Main Results:

  • Golgi-associated H-Ras activation occurs in situ with distinct kinetics compared to plasma membrane activation.
  • Endoplasmic reticulum-tethered oncogenic H-Ras preferentially activated ERK and Akt pathways.
  • Golgi-tethered oncogenic H-Ras predominantly activated the Jun-NH2-terminal kinase (JNK) pathway.

Conclusions:

  • Subcellular localization of Ras dictates the engagement of specific downstream effector pathways.
  • Golgi-associated Ras activation may involve second messengers and Golgi-localized guanine nucleotide exchange factors like Ras-GRP.

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