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Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration

Elena Rainero1, Patrick T Caswell, Patricia A J Muller

  • 1Beatson Institute for Cancer Research, G61 1BD Glasgow, Scotland, UK.

The Journal of Cell Biology
|January 25, 2012
PubMed

Insights

Diacylglycerol kinase α (DGK-α) generates phosphatidic acid (PA), which is essential for tumor cell invasion by controlling Rab-coupling protein (RCP) and α5β1 integrin recycling. This mechanism links mutant p53 or αvβ3 inhibition to cancer cell migration.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Oncogenic mutations in p53 and inhibition of αvβ3 integrin promote tumor cell invasion.
  • This process involves enhanced endosomal recycling of α5β1 integrin, regulated by the Rab11 effector, Rab-coupling protein (RCP).

Purpose of the Study:

  • To investigate the role of diacylglycerol kinase α (DGK-α) in regulating RCP-dependent α5β1 integrin recycling and tumor cell invasion.
  • To elucidate the mechanism by which DGK-α, phosphatidic acid (PA), and RCP mediate cancer cell migration.

Main Methods:

  • Investigated the role of DGK-α in RCP mobilization and tethering to invasive pseudopods.
  • Utilized constitutive-active DGK-α mutants and RCP mutants lacking the PA-binding C2 domain.
  • Assessed tumor cell invasion through three-dimensional matrices.

Main Results:

  • DGK-α is required for RCP mobilization to pseudopod tips and subsequent α5β1 integrin recycling, driving tumor cell invasiveness.
  • Constitutive-active DGK-α expression promoted RCP-dependent invasion independently of mutant p53 or αvβ3 inhibition.
  • An RCP mutant unable to bind PA failed to tether at pseudopod tips, disrupting invasion.

Conclusions:

  • Generation of PA by DGK-α is crucial for linking mutant p53 or αvβ3 inhibition to RCP.
  • DGK-α-mediated PA production is essential for RCP to drive α5β1 integrin trafficking required for tumor cell invasion in 3D matrices.

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