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Mutations in the focal adhesion targeting region of deleted in liver cancer-1 attenuate their expression and function

Yi-Chun Liao1, Yi-Ping Shih, Su Hao Lo

  • 1Department of Biochemistry and Molecular Medicine, Center for Tissue Regeneration and Repair, University of California, Davis, Sacramento, California 95817, USA.

Cancer Research
|October 3, 2008
PubMed

Insights

Mutations in the Deleted in liver cancer-1 (DLC-1) tumor suppressor gene can impair its function. This study identified mutations in the focal adhesion targeting region that reduce DLC-1

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Deleted in liver cancer-1 (DLC-1) is a tumor suppressor gene encoding a Rho GTPase-activating protein (RhoGAP).
  • DLC-1 is frequently downregulated in various cancers.
  • DLC-1's tumor suppressive activity relies on its recruitment to focal adhesions.

Purpose of the Study:

  • To investigate mutations within the focal adhesion targeting (FAT) region of DLC-1.
  • To determine the impact of these mutations on DLC-1 expression, localization, and function.
  • To explore the role of the FAT region in regulating DLC-1's RhoGAP activity.

Main Methods:

  • Mapping of the DLC-1 FAT region (amino acid residues 201–500).
  • Sequencing of DLC-1 cDNAs and genomic DNAs encoding the FAT region from cancer patients.
  • Functional analysis of identified DLC-1 mutants, including assessment of focal adhesion localization, tumor cell growth suppression, and RhoGAP activity.

Main Results:

  • Several missense and nonsense mutations were detected in the DLC-1 FAT region.
  • Identified mutations did not affect DLC-1's focal adhesion localization.
  • Two mutants, T301K and S308I, exhibited impaired tumor cell growth suppression and significantly reduced RhoGAP activity, indicating a regulatory role for the FAT region in RhoGAP function.

Conclusions:

  • Mutations in the DLC-1 FAT region can lead to loss of function, contributing to tumorigenesis.
  • The DLC-1 FAT region contains a regulatory element allosterically controlling its RhoGAP activity.
  • These findings highlight the importance of DLC-1 integrity for tumor suppression and provide insights into its regulatory mechanisms.

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