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The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation

Rolf-Peter Scholz1, Johan O R Gustafsson, Peter Hoffmann

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

Experimental Cell Research
|November 20, 2010
PubMed

Insights

Protein kinase D (PKD) phosphorylates the tumor suppressor Deleted in liver cancer 1 (DLC1) at serine 807. This phosphorylation negatively regulates DLC1

Area of Science:

  • Molecular oncology
  • Cell signaling

Background:

  • Deleted in liver cancer 1 (DLC1) is a crucial tumor suppressor protein often downregulated in various cancers.
  • The Rho GTPase activating protein (GAP) domain of DLC1 is essential for its tumor-suppressive functions, but regulatory mechanisms remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms regulating DLC1 function.
  • To identify novel regulatory sites and kinases involved in DLC1 modulation.

Main Methods:

  • Mass spectrometry was employed to identify novel phosphorylation sites on DLC1.
  • A phospho-S807-specific antibody was generated to detect phosphorylation at this site.
  • Protein kinase D (PKD) was identified as the kinase responsible for DLC1 phosphorylation at serine 807 in cellular models.

Main Results:

  • A novel phosphorylation site at serine 807 within the DLC1 GAP domain was identified.
  • Protein kinase D (PKD) was confirmed to phosphorylate DLC1 at serine 807 in intact cells.
  • While in vitro GAP activity was unaffected, a serine-to-alanine mutant of DLC1 at position 807 exhibited enhanced inhibition of colony formation compared to wild-type DLC1.

Conclusions:

  • PKD-mediated phosphorylation of DLC1 at serine 807 negatively regulates its cellular functions.
  • This regulatory mechanism provides new insights into DLC1's role in tumor suppression.
  • Targeting the PKD-DLC1 interaction could represent a novel therapeutic strategy in cancer treatment.

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