DOCK3 and Associated Diseases
Through affecting actin and microscopic alterations causing targeted formation of cellular neural axons and strong cell adhesion, dedicator of cytokinesis 3 (DOCK3) has been associated with the development of several neurological diseases and cancers. Gene therapy, as a specific targeted intervention, is a promising tool for investigating new therapeutic approaches. With skilled gene therapy development experience and an advanced technical team, Creative Biolabs is committed to providing comprehensive gene therapy products and services to help our clients conduct research into gene editing-based therapeutic options.
Overview of DOCK3 Gene
DOCK3, also known as MOCA (Modifier of cell adhesion) or PBP (Presenilin-binding protein), is located on chromosome 3 and encodes cytoplasmic splitting action factor 3. As a member of the guanylate exchange factor family DOCK180, expressed DOCK3 specifically activates Rac1 in Rho GTPase by forming a complex with p130 Cas and Crk that leads to adhesion blobs, thereby participating in the protein binding processes and aggregation in the central nervous system and growth cones. The activated Rac1 further participates and regulates several processes involving cytoskeleton and intercellular interactions in interaction with WAVE family proteins, including actin polymerization, signal transduction on integral proteins, formation of plate and filamentous pseudopods, N-cadherin-dependent cell adhesion, phagocytosis, and cell migration. In addition, DOCK3 is also expressed in the cell membrane and cytoplasm of frontal, temporal, occipital, and brainstem by binding to phosphatidylinositol and is mainly co-expressed with neurons but not glial cells. Therefore, given the aforementioned regulatory role involved in actin cytoskeletal remodeling, DOCK3 has emerged as one of the potential targets to study various brain diseases and tumors.
Fig.1 Proposed role of DOCK3 in BDNF-mediated axonal outgrowth. (Namekata, 2010)
DOCK3 and Alzheimer's disease (AD)
Aberrant phosphorylation of Tau proteins leading to the formation of insoluble aggregates is one of the major case markers of AD, which is induced by the dysregulation of protein kinases of different signaling pathways. DOCK3 is able to play an influential regulatory role in the dynamic function of the cytoskeletal protein Actin through the activation of Rac1. This damage to the cytoskeletal system was observed in a DOCK3 knockout mouse model, inducing abnormal phosphorylation of Tau and the formation of pathological neurofibrillary tangles of which it is a major component. Meanwhile, the detection of co-localization of DOCK3 with neurofibrillary tangle structures further emphasizes the close relationship between DOCK3 deletion and AD occurrence, providing new ideas for future research on related drugs.
Fig.2 Schematic illustration of the APP and PS-mediated neuronal death signal pathways. (Tachi, 2012)
DOCK3 and Epilepsy
Epilepsy is triggered by abnormal synaptic transmission and neural network formation in brain tissue that activates overexcited neurons. Overexpression of DOCK3, a downstream component of BDNF signaling, stimulates neuronal axon growth to increase the risk of epilepsy and other neurological diseases, which also involves activation of CRMP-2 to mediate microtubule assembly upon binding to GSK-3-β on the cell membrane. Researchers have identified overexpression of DOCK3 and pathological hyperexcitability of neurons mediated by NMDA receptors in brain tissue from patients with drug-resistant temporal lobe epilepsy and in a rat model of pilocarpine-induced epilepsy. In contrast, after expression deletion or shRNA interference with DOCK3, axonal degeneration and loss of functional integrity occurred, accompanied by a reduction in granule cell mossy fiber sprouting.
DOCK3 and Glaucoma
In the mouse model of IOP glaucoma, DOCK3 inhibits neuronal cell death and alleviates optic nerve damage by stimulating axonal regeneration, which is achieved by inhibiting NR2B-mediated glutamate neurotoxicity and oxidative stress.
DOCK3 and Cancer
DOCK3 is able to form a complex with β-catenin, a key effector protein of Wnt, resulting in decreased levels of β-catenin in the nucleus and increased binding at the cell membrane, thereby inhibiting the transcription of Wnt target genes and interfering with the proliferation and invasion of tumor cells. However, researchers found that DOCK3 mediates epithelial-mesenchymal transition and promotes fibrosis based on the promotion of collagen and smooth muscle actin expression and the inhibition of E-cadherin protein expression during lung interstitial fibrosis. Meanwhile, miR-486, which was screened to have a complementary site to the 3'UTR end of DOCK3, was able to target down-regulate its expression to counteract fibrosis. Similarly, miR-512-3p may inhibit the ability of DOCK3 to induce cancer cell adhesion and invasion in non-small cell lung cancer.
Fig.3 Schematic diagram of the main mechanisms involved in DOCK3 regulation of cancer cell motility. (Cui, 2016)
The expression and deletion of DOCK3 considerably affect the development and progression of a variety of diseases related to AD, epilepsy, and cancer. Creative Biolabs has the most complete service platform and the most professional team of scientists to provide customized services for DOCK3-related gene therapy according to your needs. Please contact us to advance your research.
References
- Namekata, K.; et al. DOCK3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci U S A. 2010, 107(16): 7586-7591.
- Tachi, N.; et al. MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid β precursor protein and presenilins. Biochem J. 2012, 442(2): 413-422.
- Cui, H.Y.; et al. CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling. Oncotarget. 2016, 7(5): 5613-5629.
