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Related Experiment Videos

Compartmentalized signalling of Ras.

M R Philips1

  • 1Department of Medicine, Cell Biology and Pharmacology, NYU School of Medicine, New York, NY, USA. philim01@med.nyu.edu

Biochemical Society Transactions
|July 27, 2005
PubMed
Summary

Ras proteins signal from various cellular membranes, not just the plasma membrane. Their location, including the Golgi and mitochondria, dictates distinct signaling outputs and cellular outcomes like apoptosis.

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Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • Ras proteins are key regulators of cellular signaling pathways.
  • Post-translational modifications, including CAAX box processing, target Ras to cellular membranes.
  • Nascent Ras proteins traffic through endomembranes to reach the plasma membrane and Golgi apparatus.

Purpose of the Study:

  • To investigate the signaling capabilities of Ras proteins on internal cellular membranes.
  • To develop a tool for visualizing Ras activation dynamics in living cells.
  • To understand how Ras localization influences downstream signaling pathways and cellular functions.

Main Methods:

  • Development of a fluorescent probe to monitor Ras activation in real-time.
  • Cellular imaging techniques to track Ras localization and activity.
  • Genetic and biochemical analyses to map signaling pathways involved in Ras activation.

Main Results:

  • Growth factors induce rapid Ras activation at the plasma membrane, followed by delayed activation on the Golgi apparatus.
  • A pathway involving phospholipase Cgamma (PLCγ), diacylglycerol (DAG), and Ras guanyl nucleotide-releasing protein 1 (RasGRP1) mediates Golgi Ras activation.
  • K-Ras phosphorylation by protein kinase C (PKC) alters its subcellular localization, including accumulation on the outer mitochondrial membrane.
  • Phosphorylated K-Ras on mitochondria promotes apoptosis.

Conclusions:

  • Ras signaling is not confined to the plasma membrane; internal membrane localization is critical for its function.
  • Differential localization of activated Ras leads to the activation of distinct downstream signaling pathways.
  • Subcellular localization dynamically regulates Ras signaling output, impacting cellular fate decisions such as apoptosis.

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