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

Abstract

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.

Spermidine Ameliorates Neurodegeneration in a Mouse Model of Normal Tension Glaucoma

“…11 Interestingly, Dock3 signaling is enhanced by brain-derived neurotrophic factor (BDNF), which induces neuroprotection, axonal outgrowth and neurogenesis. 31,[45][46][47] A recent study has shown that a novel phosphine-borane complex promotes RGC protection through the induction of BDNF and activation of the extracellular signal-regulated kinases (ERK) 1/2.…”

Dock protein family in brain development and neurological disease

“…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 .…”

“…The most well known regulation of the Dock family, in particular Dock-A and Dock-B members, is the interaction with ELMO 29 , 38 , 39 , 66 , 67 . ELMO binds to the SH3 domain of Docks, thus leading to the release of the autoinhibitory status of Docks and exposure of their DHR2 domain for Rac activation 67 .…”

“…Dock proteins participate in a number of signaling pathways, among which Trk receptors, Neuregulin-ErB, Eph-Ephrin, and Wnt mediated signaling pathways are important in nervous system 11 , 29 , 33 , 48 , 62 , 73 . Docks can be directly or indirectly recruited to these signaling receptor complexes to be activated (Table 2).…”

The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases

“…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.…”