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Paxillin kinase linker (PKL) regulates Vav2 signaling during cell spreading and migration

Matthew C Jones1, Kazuya Machida, Bruce J Mayer

  • 1Department of Cell and Developmental Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210-2375, USA.

Molecular Biology of the Cell
|April 26, 2013
PubMed

Insights

The proto-oncogene Vav2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Rho GTPases regulate cell migration machinery dynamics.
  • Guanine nucleotide exchange factors (GEFs) activate Rho GTPases.
  • GTPase-activating proteins (GAPs) negatively regulate Rho GTPases.
  • Spatial and temporal regulation of GEFs and GAPs is poorly understood.

Purpose of the Study:

  • Investigate the regulation of Vav2, a GEF for Rac1, RhoA, and Cdc42.
  • Elucidate the role of the ArfGAP PKL (GIT2) in Vav2 activity.
  • Determine the involvement of Vav2 and PKL in cell migration signaling pathways.

Main Methods:

  • Phosphorylation-dependent interaction assays.
  • Integrin engagement and epidermal growth factor (EGF) stimulation experiments.
  • Vav2 knockdown studies to assess effects on cell migration.

Main Results:

  • PKL regulates Vav2 activation downstream of integrin and EGF signaling.
  • Vav2 controls the redistribution of PKL and β-PIX to focal adhesions.
  • A feedforward signaling loop coordinates PKL-dependent Vav2 activation and PKL localization.
  • Vav2 is essential for PKL and β-PIX localization to the leading edge of migrating cells.

Conclusions:

  • Vav2 activity is regulated by a phosphorylation-dependent interaction with PKL.
  • Vav2 and PKL form a feedforward loop influencing their localization and activation.
  • Vav2 is crucial for directional cell migration, polarization, and PKL/β-PIX signaling coordination.

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