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DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling

Rolf-Peter Scholz1, Jennifer Regner, Anke Theil

  • 1University of Stuttgart, Institute of Cell Biology and Immunology, Allmandring 31, 70569 Stuttgart, Germany.

Journal of Cell Science
|December 11, 2008
PubMed

Insights

Protein kinase activation stimulates 14-3-3 protein binding, inhibiting DLC1 tumor suppressor activity. This binding also blocks DLC1’s movement between the nucleus and cytoplasm, revealing a new regulatory mechanism.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Cancer research

Background:

  • Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) with tumor suppressor functions.
  • DLC1 is downregulated in various cancer types.
  • Mechanisms regulating DLC1 activity remain largely uninvestigated.

Purpose of the Study:

  • To investigate the molecular mechanisms controlling DLC1 activity and localization.
  • To identify how DLC1’s tumor suppressor function is regulated.

Main Methods:

  • Investigated DLC1 association with 14-3-3 proteins upon phorbol ester treatment.
  • Utilized in vitro assays to assess DLC1 GAP activity.
  • Examined DLC1 nucleocytoplasmic shuttling in response to protein kinase activation and 14-3-3 protein coexpression.

Main Results:

  • Phorbol ester-induced activation of protein kinase C and D stimulates DLC1 binding to 14-3-3 proteins via Ser327 and Ser431.
  • 14-3-3 binding inhibits DLC1’s Rho-GAP activity, promoting Rho signaling.
  • 14-3-3 binding blocks DLC1 nucleocytoplasmic shuttling, potentially by masking a nuclear localization sequence.

Conclusions:

  • 14-3-3 protein binding represents a novel mechanism for regulating DLC1 activity and subcellular localization.
  • This regulation impacts DLC1’s tumor suppressor function by modulating Rho signaling.
  • Understanding DLC1 regulation by 14-3-3 proteins offers potential therapeutic targets in cancer.

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