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KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression

Syed M Ahmed1, Brigitte L Thériault, Maruti Uppalapati

  • 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A1, Canada.

The Journal of Cell Biology
|December 5, 2012
PubMed

Insights

Kinesin KIF14 tethers Radil to microtubules, inhibiting Rap1-mediated integrin activation. KIF14 depletion increases cell spreading and migration, impacting breast cancer progression and metastasis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The small GTPase Rap1 controls cell adhesion and migration via inside-out integrin activation.
  • Radil is a Rap1 effector involved in cell spreading and migration, but its regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which Radil regulates Rap1-mediated integrin activation.
  • To explore the role of KIF14 in Radil function and its implications in cancer.

Main Methods:

  • Co-immunoprecipitation to assess KIF14-Radil interaction.
  • Immunofluorescence microscopy to visualize Radil localization on microtubules.
  • Cell migration and invasion assays.
  • In vivo metastasis models in mice.

Main Results:

  • KIF14 directly associates with the PDZ domain of Radil and tethers it to microtubules.
  • KIF14 negatively regulates Rap1-mediated inside-out integrin activation.
  • KIF14 depletion enhances cell spreading, alters focal adhesion dynamics, and inhibits cell migration and invasion.
  • Radil is crucial for breast cancer cell proliferation and metastasis.
  • Concurrent upregulation of Rap1 activity and KIF14 levels promotes tumor progression.

Conclusions:

  • KIF14 acts as a negative regulator of Rap1-Radil signaling by controlling Radil localization.
  • The KIF14-Radil axis is a critical determinant of cell adhesion, migration, and invasion.
  • Targeting the KIF14-Radil interaction may offer therapeutic strategies for cancers with elevated Rap1 activity.

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