Isolation and Characterization of Novel Presenilin Binding Protein

Kashiwa, Atsushi; Yoshida, Hirotaka; Lee, Soon; Paladino, Toni; Liu, Yuanbin; Chen, Qi; Dargusch, Richard; Schubert, David; Kimura, Hideo

doi:10.1046/j.1471-4159.2000.0750109.x

Cited by 68 publications

(100 citation statements)

References 20 publications

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“…DOCK3/MOCA belongs to the DOCK180 family of proteins and had been shown to be localized specifically in neurons. 8 The closely related members of the family: DOCK180 (also known as DOCK1), DOCK4 or DOCK7 had no effect in our system, indicating that DOCK3 is specifically involved in mesenchymal-type movement of melanoma cells. 7 Farnesylated DOCK3, which was shown to be localized in the plasma membrane, enhanced the activation of Rac1 and JNK more markedly than wild-type DOCK3, and cells expressing farnesylated DOCK3 showed flattened morphology similar to those expressing a constitutive active mutant of Rac1.…”

Section: Dock3mentioning

confidence: 70%

Rho-GTPase signaling drives melanoma cell plasticity

Sanz-Moreno¹,

Marshall²

2009

Cell Cycle

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Section: Dock3mentioning

confidence: 70%

Rho-GTPase signaling drives melanoma cell plasticity

Sanz-Moreno¹,

Marshall²

2009

Cell Cycle

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“…On the other hand, GSK-3␤ activity has been associated with many psychiatric and neurodegenerative diseases, such as Alzheimer's disease, schizophrenia and autism spectrum disorders, and it has become increasingly apparent that GSK-3␤ might be a common therapeutic target for different classes of psychiatric drugs (Hur and Zhou, 2010). Intriguingly, Dock3 was initially identified to bind to presenilin 1, a major causative gene of earlyonset familial Alzheimer's disease (Kashiwa et al, 2000;Bertram et al, 2010). In addition, Dock3 expression is significantly reduced in Alzheimer's disease (Kashiwa et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, Dock3 was initially identified to bind to presenilin 1, a major causative gene of earlyonset familial Alzheimer's disease (Kashiwa et al, 2000;Bertram et al, 2010). In addition, Dock3 expression is significantly reduced in Alzheimer's disease (Kashiwa et al, 2000). Because the intracellular localization of Dock3 modulates GSK-3␤ activity (Figs.…”

Section: Discussionmentioning

confidence: 99%

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolinhomologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3␤ (GSK-3␤) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3␤ and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3␤ was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.

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“…Several Dock proteins have already been linked to various neuropsychiatric and neurodegenerative diseases, including autism spectrum disorder, schizophrenia, and Parkinson's disease. Dock3 (also known as modifier of cell adhesion), a member of the DOCK-B subfamily, was originally discovered as a presenilin-1 (PS1)-interacting protein, highly expressed in the cortex and hippocampus, which hinted at a possible role in AD pathogenesis [83]. Indeed, analysis of postmortem brain tissue patients revealed a significant decrease in total Dock3 protein in AD brains.…”

Section: Dedicator Of Cytokinesismentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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Isolation and Characterization of Novel Presenilin Binding Protein

Cited by 68 publications

References 20 publications

Rho-GTPase signaling drives melanoma cell plasticity

Rho-GTPase signaling drives melanoma cell plasticity

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

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