DRG2 knockdown induces Golgi fragmentation via GSK3β phosphorylation and microtubule stabilization

Mani, Muralidharan; Thao, Dang Thi; Kim, Beom Chang; Lee, Unn Hwa; Kim, Dong Jun; Jang, Seung‐Ho; Back, Sung Hoon; Lee, Byung Ju; Cho, Wha Ja; Han, In-Seob; Park, Jeong Woo

doi:10.1016/j.bbamcr.2019.06.003

Cited by 11 publications

(17 citation statements)

References 74 publications

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“…Previously, we have reported that DRG2 depletion induces cell cycle arrest and mitochondrial dysfunction , leading to inhibition of cell growth. In addition, it has been reported that DRG2 interacts with Rab5 on early endosome and DRG2 depletion inhibits endosome trafficking , enhances the Akt signal from endosome, and inhibits perinuclear Golgi stacking and cell migration . In this study, we found that DRG2 depletion inhibited growth of melanoma cells.…”

Section: Discussionsupporting

confidence: 58%

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DRG2 supports the growth of primary tumors and metastases of melanoma by enhancing VEGF‐A expression

et al. 2019

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Malignant metastatic melanoma (MM) is the most lethal of all skin cancers, but detailed mechanisms for regulation of melanoma metastasis are not fully understood. Here, we demonstrated that developmentally regulated GTP-binding protein 2 (DRG2) is required for the growth of primary tumors and for metastasis. DRG2 expression was significantly increased in MM compared with primary melanoma (PM) and dysplastic nevi. A correlation between DRG2 expression and poor disease-specific survival in melanoma patients was also identified. Furthermore, inhibition of DRG2 suppressed the binding of Hypoxia-inducible factor 1a to the VEGF-A promoter region, expression of vascular endothelial growth factor (VEGF)-A, and formation of endothelial cell tubes. In experimental mice, DRG2 depletion inhibited the growth of PM and lung metastases and increased survival. These results identify DRG2 as a critical regulator of VEGF-A expression and of growth of PMs and lung metastases.

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Section: Discussionsupporting

confidence: 58%

“…DRG2 upregulates VEGF‐A by enhancing transcription. Previously, we have reported that DRG2 regulates endosome trafficking and microtubule dynamics by interacting with Rab5 on endosome. Interestingly, we here observed that DRG2 depletion inhibits nuclear translocation of HIF‐1α and HIF‐1α‐mediated transcription of VEGF‐A .…”

Section: Discussionmentioning

confidence: 99%

DRG2 supports the growth of primary tumors and metastases of melanoma by enhancing VEGF‐A expression

et al. 2019

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“…DRG2 has been suggested to play a key role in cell cycle regulation in cell growth and differentiation control [28,29] inducing mitochondrial function and affecting cell migration via the regulation of MT dynamics and Golgi fragmentation [19,30] in overexpression or knockdown experiments. These in vitro results suggest that DRG2 may play important roles in in vivo developmental stages and behavioral differences.…”

Section: Discussionmentioning

confidence: 99%

“…DRG2 interacts with Rab5 on vesicular endosomes and is involved in the regulation of endosomal Rab5 activity and endosome trafficking [18]. DRG2 depletion extends the expression of EGFR on Rab5-containing endosomes and increases the activity of Akt and inhibitory phosphorylation of GSK3β, thus reducing the phosphorylation of Tau, which leads to an enhanced interaction between Tau and MT and hyperstabilization of MTs [19]. Considering the involvement of Tau [20] and MTs [7] in neurodegenerative diseases, we predict that DRG2 may play an important role in the pathogenesis of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release

Lim

Kim

et al. 2019

IJMS

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Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

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“…The causes of Golgi fragmentation in neurodegenerative diseases may be diverse. First, alteration of the microtubule and microfilament stabilization may also be the cause (37). In Alzheimer's disease and other tauopathies, tau-induced microtubule-bundling may result in Golgi fragmentation (38).…”

Section: Structural and Functional Changes Of The Golgi Apparatus In Diseasesmentioning

confidence: 99%

The role of the Golgi apparatus in disease (Review)

Liu

Huang

et al. 2021

Int J Mol Med

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The Golgi apparatus is known to underpin many important cellular homeostatic functions, including trafficking, sorting and modifications of proteins or lipids. These functions are dysregulated in neurodegenerative diseases, cancer, infectious diseases and cardiovascular diseases, and the number of disease-related genes associated with Golgi apparatus is on the increase. Recently, many studies have suggested that the mutations in the genes encoding Golgi resident proteins can trigger the occurrence of diseases. By summarizing the pathogenesis of these genetic diseases, it was found that most of these diseases have defects in membrane trafficking. Such defects typically result in mislocalization of proteins, impaired glycosylation of proteins, and the accumulation of undegraded proteins. In the present review, we aim to understand the patterns of mutations in the genes encoding Golgi resident proteins and decipher the interplay between Golgi resident proteins and membrane trafficking pathway in cells. Furthermore, the detection of Golgi resident protein in human serum samples has the potential to be used as a diagnostic tool for diseases, and its central role in membrane trafficking pathways provides possible targets for disease therapy. Thus, we also introduced the clinical value of Golgi apparatus in the present review.

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DRG2 knockdown induces Golgi fragmentation via GSK3β phosphorylation and microtubule stabilization

Cited by 11 publications

References 74 publications

DRG2 supports the growth of primary tumors and metastases of melanoma by enhancing VEGF‐A expression

DRG2 supports the growth of primary tumors and metastases of melanoma by enhancing VEGF‐A expression

DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release

The role of the Golgi apparatus in disease (Review)

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