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

Yi Chun Liao, Yi Ping Shih, Su Hao Lo

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Deleted in liver cancer-1 (DLC-1) is a RhoGTPase-activating protein (RhoGAP) domain containing tumor suppressor that is often down-regulated in various cancer types. Previously, we have shown that DLC-1 is recruited to focal adhesions by binding to the Src homology2 domains of tensins and the focal adhesion localization is critical for the tumor suppression activityof DLC-1. To investigate whether mutations in the focal adhesion targeting (FAT) region might occur and attenuate the expression, localization, and function of DLC-1, we have first mapped the FAT region to the amino acid residues from 201 to 500, and then sequenced cDNAs and genomic DNAs encoding the FAT region from cancer patients. Several missense and nonsense mutations were detected. All missense mutations were further examined for the potential effect on the function of DLC-1. Although these mutations did not seem to affect the focal adhesion localization of DLC-1, the activities of suppressing tumor cell growth were impaired in two mutants: T301K and S308I. Consistent with the fact that the RhoGAP activityof DLC-1 is essential for inhibiting tumor cell growth, the RhoGAP activities were significantly reduced in these mutants, suggesting that the FAT region also contains a regulatory element for its COOH-terminal RhoGAP domain. Our studies have shown that mutations in DLC-1 may lead to loss of function and contribute to the tumorigenesis, and have revealed an allosteric regulation site for its RhoGAP activity.

Original languageEnglish (US)
Pages (from-to)7718-7722
Number of pages5
JournalCancer Research
Volume68
Issue number19
DOIs
StatePublished - Oct 1 2008

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Focal Adhesions
Liver Neoplasms
Mutation
Neoplasms
Missense Mutation
Allosteric Regulation
Allosteric Site
Proteins
Nonsense Codon
Growth
Carcinogenesis
Complementary DNA
Amino Acids
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mutations in the focal adhesion targeting region of deleted in liver cancer-1 attenuate their expression and function. / Liao, Yi Chun; Shih, Yi Ping; Lo, Su Hao.

In: Cancer Research, Vol. 68, No. 19, 01.10.2008, p. 7718-7722.

Research output: Contribution to journalArticle

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