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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

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Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis

Francesco Baschieri1, Stefano Confalonieri2, Giovanni Bertalot3

  • 11] University of Konstanz, 78464 Konstanz, Germany [2] Biotechnology Institute Thurgau, University of Konstanz, Kreuzlingen CH-8280, Switzerland.

Nature Communications
|September 12, 2014
PubMed

Insights

A newly identified GM130-RasGRF complex regulates Cdc42 at the Golgi, impacting cell polarity and migration. This discovery reveals a link between Golgi Cdc42, polarity, and cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The small GTPase Cdc42 is crucial for cell polarity.
  • Spatial regulation of Cdc42 and its specific pools remain poorly understood in mammals.
  • The Golgi apparatus's role in Cdc42 spatial regulation is largely unknown.

Purpose of the Study:

  • To identify regulators of spatial Cdc42 pools at the Golgi.
  • To investigate the functional relevance of Golgi-localized Cdc42 in cell polarity and migration.
  • To explore the connection between Golgi regulators, Cdc42, and cancer.

Main Methods:

  • Silencing of GM130 using RNA interference.
  • Assessment of Cdc42 localization and activity at the Golgi and cell surface.
  • Analysis of cell migration dynamics and front-rear polarity.
  • Investigation of the Ras-ERK pathway activation.
  • Evaluation of E-cadherin expression levels.
  • Correlation of GM130 expression with patient cancer data.

Main Results:

  • A GM130-RasGRF complex was identified as a Golgi-specific regulator of Cdc42.
  • GM130 silencing led to RasGRF-dependent inhibition of Golgi Cdc42, without affecting cell surface Cdc42.
  • Active Golgi Cdc42 is essential for maintaining asymmetric Cdc42-GTP distribution during directional cell migration.
  • GM130 depletion induced RasGRF-dependent Ras-ERK pathway activation and E-cadherin downregulation.
  • Loss of GM130 expression is frequent in colorectal and breast cancers.

Conclusions:

  • The GM130-RasGRF complex is a novel regulator of Golgi Cdc42, crucial for cell polarity.
  • This pathway influences directional migration and epithelial identity.
  • Disruption of this complex contributes to tumorigenesis, with implications for colorectal and breast cancers.

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