Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Genes to Cells (Impact Factor: 2.81). 06/2012; 17(8):688-97. DOI: 10.1111/j.1365-2443.2012.01616.x
Source: PubMed


Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways.

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Available from: Takayuki Harada, Jul 20, 2014
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    • "Based on its high sequence homology with Dock1/180 (51% homology with the SH3 domain; 45% homology with the DHR1 domain, 42% homology with the DHR2 domain, and the inclusion of a Crk binding site), Dock3/MOCA was identified as a member of the Dock180 superfamily of proteins (Cote and Vuori, 2002). Dock3/MOCA was initially thought to be devoid of GEF activity ; however, it was subsequently shown to induce RAC-GTP loading through the interaction of its SH3 domain with ELMO1 (engulfment and cell motility protein 1), a mechanism shared with Dock1/180 (Grimsley et al., 2004; Namekata et al., 2004, 2012). Although the exact mechanism remains uncertain, PBP stimulates phosphorylation of tau at Ser199 (Chen et al., 2001) suggesting a direct mechanism in leading to the pathological hyper-phosphorylation of tau in Alzheimer's disease. "
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    ABSTRACT: Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3' untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.
    Frontiers in Cellular Neuroscience 09/2014; 8. DOI:10.3389/fncel.2014.00282 · 4.29 Impact Factor
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    • "We previously stimulated axonal regeneration by activating signaling pathways involving dedicator of cytokinesis 3 (Dock3), an atypical guanine nucleotide exchange factor that is predominantly expressed in neurons [15] [17]. We found that the brain-derived neurotrophic factor (BDNF)-Dock3 pathway in RGC growth cones promotes axonal outgrowth by stimulating dual pathways: the Rac1-mediated actin polymerization pathway and the glycogen synthase kinase-3␤ (GSK-3␤)-mediated microtubule assembly pathway [14] [15] [18]. In addition, overexpression of Dock3 protects RGCs from oxidative stress and glutamate neurotoxicity [16]. "
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    ABSTRACT: The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.
    Neuroscience Letters 08/2014; 581. DOI:10.1016/j.neulet.2014.08.034 · 2.03 Impact Factor
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    • "Several molecular mechanisms have been revealed underlying Dock3-mediated neurite and axon growth. First, Dock3 associates with ELMO and RhoG to form the conventional ternary Dock-ELMO-RhoG complex, which is important for Rac1 activation during brain-derived neurotrophic factor (BDNF)-TrkB mediated neurite outgrowth.29 Moreover, Dock3 regulates actin cytoskeleton, microtubule assembly, and cell–cell adhesion by interacting with or regulating WAVE (Wiskott-Aldrich syndrome protein family verprolin-homologous), GSK-3β (glycogen synthase kinase 3β), and N-cadherin, respectively.30-32 "
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    ABSTRACT: The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed.
    Communicative & integrative biology 11/2013; 6(6):e26839. DOI:10.4161/cib.26839
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