DOCK4, a GTPase activator, is disrupted during tumorigenesis.
Open accessAbstract
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.
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DOCK4 is the only member of the DOCK family that is capable of activating RAP1.
“DOCK4 is the only member of the DOCK family that is capable of activating RAP1 (Yajnik et al. 2003; Shi 2013)”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Yajnik et al. 2003
The Results report that wild-type DOCK4 activated Rap GTPase more than fivefold in transfected cells, supporting its ability to activate Rap1. The paper contrasts DOCK4 with family members associated with Rac signaling, but does not establish that no other DOCK family member can activate Rap1. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDOCK4 activates RAC and RAP1 GTPases.
“DOCK4 activates RAC and RAP1 GTPases (82).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [82]
The Results ('Activation of Rap GTPase by DOCK4') report strong Rap activation by wild-type DOCK4, but explicitly state that it had no effect on Rac. Rac activation was observed with the tumor-associated Pro1718Leu mutant, not wild-type DOCK4. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDock4 is capable of activating Rap1.
“Interestingly, evidence from other system suggests that Dock4 is also capable of activating Rap1 (Yajnik et al., 2003), another small G protein involved in cell adhesion and growth.”
From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Yajnik et al., 2003
DOCK4 was first identified as a Rap GTPase activator that can enhance the formation of adherent junctions between cells, mutations of which was found to confer the loss of cell junction and an invasive phenotype in cancer.
“It was first identified as a Rap GTPase activator that can enhance the formation of adherent junctions between cells, mutations of which was found to confer the loss of cell junction and an invasive phenotype in cancer (37).”
From miR-33b-3p Acts as a Tumor Suppressor by Targeting DOCK4 in Prostate Cancer (2021) · cites this paper as [37]
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References 63 · Cited by 230
Research works printed but not linked: 5
- [1]1. Albert, M.L. ∙ Kim, J.I. ∙ Birge, R.B. αvβ5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells Nat. Cell Biol. 2000; 2:899-905 Crossref Scopus (341) Google Scholar
- [2]2. Asha, H. ∙ de Ruiter, N.D. ∙ Wang, M.G. ... The Rap1 GTPase function as a regulator of morphogenesis in vivo EMBO J. 1999; 18:605-615 Crossref Scopus (128) PubMed Google Scholar
- [3]3. Boettner, B. ∙ Govek, E.E. ∙ Cross, J. ... The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin Proc. Natl. Acad. Sci. USA. 2000; 97:9064-9069 Crossref Scopus (172) Google Scholar
- [4]4. Bos, J.L. ∙ de Rooij, J. ∙ Reedquist, K.A. Rap1 signallingadhering to new models Nat. Rev. Mol. Cell Biol. 2001; 2:369-377 Crossref Scopus (529) PubMed Google Scholar
- [6]6. Call, K.M. ∙ Glaser, T. ∙ Ito, C.Y. ... Isolation and characterization of a zinc finger polypeptide gene at the human cromosome 11 Wilms' tumor locus Cell. 1990; 60:509-520
- Authors
- Yajnik, V., Paulding, C., Sordella, R., McClatchey, A. I., Saito, M., Wahrer, D. C. R., Reynolds, P., Bell, D. W., Lake, R., van den Heuvel, S., Settleman, J., & Haber, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Haber, Daniel A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 112
- Issue
- 5
- Pages
- 673-684
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2026769136
- Cited by
- 230
- References
- 63
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 10 · 2018: 8 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 8 · 2013: 15 · 2012: 6
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (CA 58596)
- National Institute of General Medical Sciences (GM63081, R01GM063081)
- National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07191, T32DK007191)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- DOCK4, small GTPase activation, Rap1, adherens junctions, tumor progression, genomic deletions, prostate cancer, ovarian cancer, tumor invasion, osteosarcoma, missense mutations
- MeSH terms
- Animals, Bone Neoplasms, Cell Transformation, Neoplastic, Eukaryotic Cells, Genes, Regulator, Homozygote, Humans, Mice, Mutant Strains, Molecular Sequence Data, Mutation, Osteosarcoma, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Caenorhabditis elegans, Gene Deletion, Sequence Homology, Amino Acid, rap GTP-Binding Proteins, GTPase-Activating Proteins, Gene Silencing, Mice
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