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A role for Rac in Tiam1-induced membrane ruffling and invasion

F Michiels1, G G Habets, J C Stam

  • 1The Netherlands Cancer Institute, Division of Cell Biology, Amsterdam.

Nature
|May 25, 1995
PubMed

Insights

The Tiam1 gene product acts as a GDP-dissociation stimulator (GDS) for Rho-like GTPases, influencing cell behavior. This pathway, involving Rac1, is linked to tumor cell invasion and metastasis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Rho-like GTPases regulate the actin cytoskeleton, impacting cell morphology, adhesion, and motility.
  • Activation of Rho-like GTPases involves GDP-GTP exchange catalyzed by GDP-dissociation stimulator (GDS) proteins.
  • Specific GDS proteins, often containing a DBL-homology (DH) domain, activate Cdc42 or Rho, but not Rac.

Purpose of the Study:

  • To investigate the function of the invasion-inducing Tiam1 gene product.
  • To determine if Tiam1 acts as a GDS protein for Rho-like GTPases.
  • To explore the role of the Tiam1-Rac signaling pathway in cell invasion and metastasis.

Main Methods:

  • In vitro biochemical assays to assess Tiam1's GDS activity.
  • Cell-based assays in fibroblasts to observe Tiam1-induced phenotypes.
  • Use of constitutively active (V12) and dominant-negative (N17) Rac1 to probe signaling pathways.
  • Analysis of T-lymphoma cells expressing V12Rac1 to assess invasiveness.

Main Results:

  • Tiam1 functions as a GDS protein for Rho-like GTPases in vitro.
  • Tiam1 expression in fibroblasts induces phenotypes similar to activated Rac1, such as membrane ruffling.
  • These Tiam1-induced phenotypes are inhibited by dominant-negative Rac1.
  • T-lymphoma cells expressing activated Rac1 exhibit increased invasiveness.

Conclusions:

  • The Tiam1 gene product is a novel GDS protein activating Rho-like GTPases.
  • The Tiam1-Rac1 signaling pathway plays a role in regulating cell morphology and motility.
  • This pathway is potentially involved in the invasion and metastasis of tumor cells.

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