DOCK4, a GTPase Activator, Is Disrupted during Tumourigenesis.

V Yajnik, C Paulding, R Sordella, AI McClatchey, M Saito, DCR Wahrer, Paul Andrew Reynolds, DW Bell, R Lake, S van den Heuvel, J Settleman, DA Haber

Research output: Contribution to journalArticlepeer-review

202 Citations (Scopus)

Abstract

We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family encoding regulators of small GTPases. DOCK4 specifically activates Rap GTPase, enhancing the formation of adherens junctions. DOCK4 mutations are present in a subset of human cancer cell lines; a recurrent missense mutant identified in human prostate and ovarian cancers encodes a protein that is defective in Rap1 activation. The engulfment defect of C. elegans mutants lacking the CDM gene ced-5 is rescued by wild-type DOCK4, but not by the mutant allele. Expression of wild-type, but not mutant, DOCK4 in mouse osteosarcoma cells with a deletion of the endogenous gene suppresses growth in soft agar and tumor invasion in vivo. DOCK4 therefore encodes a CDM family member that regulates intercellular junctions and is disrupted during tumorigenesis.

Original languageEnglish
Pages (from-to)673-684
Number of pages12
JournalCell
Volume112
Issue number5
DOIs
Publication statusPublished - 7 Mar 2003

Keywords

  • REPRESENTATIONAL DIFFERENCE ANALYSIS
  • TUMOR-SUPPRESSOR GENE
  • E-CADHERIN
  • LYMPHOCYTE MIGRATION
  • BINDING-PROTEIN
  • PROSTATE-CANCER
  • CELL-MIGRATION
  • FREQUENT LOSS
  • ADHESION
  • COMPLEX

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