DOCK4, a GTPase activator, is disrupted during tumorigenesis.

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.

• Authors: Vijay Yajnik, Charles Paulding, Raffaella Sordella, Andrea I McClatchey, Mako Saito, Doke C R Wahrer, Paul Reynolds, Daphne W Bell, Robert Lake, Sander van den Heuvel, Jeff Settleman, Daniel A Haber
• Journal: Cell (Cell) Vol. 112 Issue 5 Pg. 673-84 (Mar 07 2003) ISSN: 0092-8674 [Print] United States
• PMID: 12628187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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