Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth
Abstract
Small GTPases of the Rho family, Rho, Rac, and Cdc42, are critical regulators of the changes in the actin cytoskeleton. Rho GTPases are typically activated by Dbl-homology (DH)-domain-containing guanine nucleotide exchange factors (GEFs). Recent genetic and biochemical studies revealed a new type of GEF for the Rho GTPases. This family is composed of 11 genes, designated as Dock1 to Dock11, and is structurally divided into four classes Dock-A, -B, -C, and -D. Dock-A and -B subfamilies are typically GEFs specific for Rac1, while the Dock-D subfamily is specific for Cdc42. Here we show that Dock6, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42 in vitro and in vivo. Furthermore, we find that, in mouse N1E-115 neuroblastoma cells, expression of Dock6 is increased following differentiation. Transfection of the catalytic Dock Homology Region-2 (DHR-2) domain of Dock6 promotes neurite outgrowth mediated by Rac1 and Cdc42. Conversely, knockdown of endogenous Dock6 by small interference RNA reduces activation of Rac1 and Cdc42 and neurite outgrowth. Taken together, these results suggest that Dock6 differs from all of the identified Dock180-related proteins, in that it is the GEF specific for both Rac1 and Cdc42 and may be one of physiological regulators of neurite outgrowth.
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DOCK10 appears to bind more than one GTPase, as evidenced by recent crystal structures in complex with CDC42 and RAC3.
“DOCK10 also appears to bind more than one GTPase as evidenced by recent crystal structures in complex with CDC42 and RAC3 (Table 1) (42, 43, 44).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [43]
DOCK6 interacts with both CDC42 and RAC1, but not RHOA, to regulate actin remodeling, manifesting as neuron growth and regeneration in the brain.
“DOCK6 is reported to interact with both CDC42 and RAC1 (but not RHOA) in order to regulate actin remodeling, manifesting as neuron growth and regeneration in the brain (40, 43).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [43]
DOCK10 is a GEF for both CDC42 and RAC GTPases.
“DOCK10 is a GEF for both CDC42 and RAC GTPases (42, 43, 44).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [43]
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References 31 · Cited by 95
- Authors
- Miyamoto, Y., Yamauchi, J., Sanbe, A., & Tanoue, A.
- Affiliations
- National Research Institute for Child Health and Development (JP)
- Corresponding author
- Yamauchi, Junji
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 313
- Issue
- 4
- Pages
- 791-804
- ISSN
- 0014-4827 (ISSN-L)
- OpenAlex
- W1978979387
- Cited by
- 95
- References
- 31
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 4 · 2012: 5
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Kowa Life Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Health Sciences Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- DOCK6, guanine nucleotide exchange factor, Rac1, Cdc42, Rho GTPases, neurite outgrowth, actin cytoskeleton, neuroblastoma cell differentiation
- MeSH terms
- Animals, Chlorocebus aethiops, Guanosine Triphosphate, Humans, Neuropeptides, Substrate Specificity, Tumor Cells, Cultured, Neurites, COS Cells, Catalytic Domain, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rac GTP-Binding Proteins, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Mice
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