DOCK4, a GTPase activator, is disrupted during tumorigenesis.
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.
Yajnik
Vijay
V
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Paulding
Charles
C
Sordella
Raffaella
R
McClatchey
Andrea I
AI
Saito
Mako
M
Wahrer
Doke C R
DC
Reynolds
Paul
P
Bell
Daphne W
DW
Lake
Robert
R
van den Heuvel
Sander
S
Settleman
Jeff
J
Haber
Daniel A
DA
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000302:isolation & purification*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D005809:Genes, Regulator / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured / Q000201:enzymology*; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C473475:Dock4 protein, mouse; D020690:GTPase-Activating Proteins; D020668:rap GTP-Binding Proteins