Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex
Open accessAbstract
Atypical Rho-guanine nucleotide exchange factors (Rho-GEFs) that contain Dock homology regions (DHR-1 and DHR-2) are expressed in a variety of tissues; however, their functions and mechanisms of action remain unclear. We identify key conserved amino acids in the DHR-2 domain that are critical for the catalytic activity of Dock-GEFs (Dock1–4). We further demonstrate that Dock-GEFs directly associate with WASP family verprolin-homologous (WAVE) proteins through the DHR-1 domain. Brain-derived neurotrophic factor (BDNF)-TrkB signaling recruits the Dock3/WAVE1 complex to the plasma membrane, whereupon Dock3 activates Rac and dissociates from the WAVE complex in a phosphorylation-dependent manner. BDNF induces axonal sprouting through Dock-dependent Rac activation, and adult transgenic mice overexpressing Dock3 exhibit enhanced optic nerve regeneration after injury without affecting WAVE expression levels. Our results highlight a unique mechanism through which Dock-GEFs achieve spatial and temporal restriction of WAVE signaling, and identify Dock-GEF activity as a potential therapeutic target for axonal regeneration.
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DOCK3 is a GEF for RAC1 and acts as a regulator of actin reorganization in neuronal tissue.
“DOCK3, a GEF for RAC1, acts as regulator of actin reorganization in neuronal tissue (69, 70, 71, 72).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [72]
WAVE1, together with the RAC GEF Dock3, were found to be downstream effectors of the BDNF-TRKB signaling cascade during axonal outgrowth.
“WAVE1, together with the RAC GEF Dock3, were found to be downstream effectors of the BDNF-TRKB signaling cascade during axonal outgrowth71.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [71]
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Xiao, Y., Peng, Y., Wan, J., Tang, G., Chen, Y., Tang, J., Ye, W.-C., Ip, N. Y., & Shi, L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.458612 · Cited by 71 · see citing works
Rho GTPases in neurodegeneration diseases
DeGeer, J., & Lamarche-Vane, N. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.06.016 · Cited by 46 · see citing works
Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Namekata, K., Harada, C., Taya, C., Guo, X., Kimura, H., Parada, L. F., & Harada, T.
- Affiliations
- Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan;
- The University of Texas Southwestern Medical Center (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- National Center of Neurology and Psychiatry (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-05
- Volume
- 107
- Issue
- 16
- Pages
- 7586-7591
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2867726
- OpenAlex
- W1977974902
- Cited by
- 84
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 8 · 2014: 9 · 2013: 10 · 2012: 6
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suzuken Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Daiwa Securities Health Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- WAVE complex, WAVE1, RhoGEF, axon growth, axonal sprouting, BDNF/TrkB signaling, Rac activation, membrane recruitment, phosphorylation, optic nerve regeneration, axon regeneration, neurotrophic signaling
- MeSH terms
- Amino Acid Sequence, Animals, Axons, Chlorocebus aethiops, Hippocampus, Humans, Molecular Sequence Data, Nerve Regeneration, Nerve Tissue Proteins, Neurons, Optic Nerve, Signal Transduction, Sequence Homology, Amino Acid, Brain-Derived Neurotrophic Factor, COS Cells, Guanine Nucleotide Exchange Factors, Proto-Oncogene Proteins c-fyn, Wiskott-Aldrich Syndrome Protein Family, Mice, Rho Guanine Nucleotide Exchange Factors
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