DOCK4, a GTPase activator, is disrupted during tumorigenesis

Cell. 2003 Mar 7;112(5):673-84. doi: 10.1016/s0092-8674(03)00155-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Caenorhabditis elegans
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Eukaryotic Cells / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / isolation & purification*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Gene Silencing / physiology
  • Genes, Regulator / genetics*
  • Homozygote
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation / genetics
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Tumor Cells, Cultured / enzymology*
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / metabolism*


  • Dock4 protein, mouse
  • GTPase-Activating Proteins
  • rap GTP-Binding Proteins

Associated data

  • GENBANK/AY233380