Developmentally regulated GTP-binding protein 2 ameliorates EAE by suppressing the development of TH17 cells

Ko, Myoung Seok; Kim, Hyo Jeong; Kim, Hong Kyung; Yoon, Nal Ae; Lee, Unn Hwa; Lee, Sang Chul; Chung, Dae Kyun; Lee, Byung Ju; Suh, Jae Hee; Cho, Wha Ja; Park, Jeong Woo

doi:10.1016/j.clim.2013.12.004

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…pcDNA6‐V5/mDRG2 (mouse DRG2) constructs were described previously . A construct 1.6 kB VEGF‐luc (deposited by Patrica A. D’Amore; Schepens Eye Research Institute, Boston, MA, USA) was purchased from Addgene (addgene.org).…”

Section: Methodsmentioning

confidence: 99%

“…The evolutionary conservation of DRGs suggests that they play an essential role in the control of cell growth and differentiation. Previously, we found that overexpression of DRG2 affects cell proliferation and apoptosis in Jurkat human T cells , inhibits T H 17 differentiation, and ameliorates experimental autoimmune encephalomyelitis in mice . We also learned that DRG2 interacts with Rab5 on endosomes and is required for Rab5 inactivation on endosomes and for recycling of transferrin (Tfn) to the plasma membrane .…”

Section: Introductionmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…pcDNA6-V5/hDRG2 (human DRG2) and pcDNA6-V5/mDRG2 (mouse DRG2) constructs were described previously ( Ko et al ., 2014 ). The following constructs were generated with PCR primers (Supplemental Table S1): pmRFPC3-hDRG2, pEGFPN1-hDRG2, and pEGFPC1-RabGAP5.…”

Section: Methodsmentioning

confidence: 99%

“…Overexpression of human DRG2 causes cell cycle arrest at the G2/M phase ( Ko et al ., 2004 ). Recently it was shown that DRG2 overexpression inhibits NF-κB function and interleukin-6 production in macrophages, as well as T H 17 differentiation, and ameliorates experimental autoimmune encephalomyelitis in mice ( Ko et al ., 2014 ). However, the precise functional role of DRGs has not been discerned.…”

Section: Introductionmentioning

confidence: 99%

Developmentally regulated GTP-binding protein 2 coordinates Rab5 activity and transferrin recycling

Mani

Lee

Yoon

et al. 2016

MBoC

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The small GTPase Rab5 regulates the early endocytic pathway of transferrin (Tfn), and Rab5 deactivation is required for Tfn recycling. Rab5 deactivation is achieved by RabGAP5, a GTPase-activating protein, on the endosomes. Here we report that recruitment of RabGAP5 is insufficient to deactivate Rab5 and that developmentally regulated GTP-binding protein 2 (DRG2) is required for Rab5 deactivation and Tfn recycling. DRG2 was associated with phosphatidylinositol 3-phosphate-containing endosomes. It colocalized and interacted with EEA1 and Rab5 on endosomes in a phosphatidylinositol 3-kinase-dependent manner. DRG2 depletion did not affect Tfn uptake and recruitment of RabGAP5 and Rac1 to Rab5 endosomes. However, it resulted in impairment of interaction between Rab5 and Rab-GAP5, Rab5 deactivation on endosomes, and Tfn recycling. Ectopic expression of shRNA-resistant DRG2 rescued Tfn recycling in DRG2-depleted cells. Our results demonstrate that DRG2 is an endosomal protein and a key regulator of Rab5 deactivation and Tfn recycling. INTRODUCTIONIntracellular vesicular trafficking contributes to diverse cellular processes, such as nutrient uptake and cell migration (Mellman, 1996). Small GTPase Rab proteins ensure the delivery of cargoes to their correct destinations by binding to various effectors, such as molecular motors and tethering factors (Stenmark, 2009). Rab5, a wellknown early endosome marker, recruits early endosome antigen 1 (EEA1; Christoforidis et al., 1999a) and regulates fusion and motility of early endosomes (Nielsen et al., 1999). Rab7 plays key roles in biogenesis and maintenance of lysosomes (Bucci et al., 2000) by making endosomes competent for fusion with lysosomes (Rink et al., 2005). Rab11 is the most prominent recycling endosome marker and regulates vesicular recycling to the plasma membrane (Ullrich et al., 1996;Grant and Donaldson, 2009). As cargoes move along endocytic pathways, the transition between early and late or recycling endosomes is mediated by Rab conversion, a process in which cascades of Rab guanine nucleotide exchange factors (GEFs) and Rab GTPase-activating proteins (GAPs) act as key regulators (Hutagalung and Novick, 2011). One well-studied Rab conversion is that from Rab5 to Rab7 as endosomes mature from early endosomes to late endosomes (Rink et al., 2005). Rab5 recruits the SAND-1(Mon1)/CZZ-1 heterodimer, which in turn recruits and activates Rab7 as the endosome matures (Poteryaev et al., 2010). Activated Rab7 recruits Rab5 GAP and facilitates inactivation and removal of Rab5 (Rink et al., 2005). Defects in Rab5 GAP inhibit the Rab5-to-Rab7 conversion and result in accumulation of large vesicles containing both Rab5 and Rab7 (Chotard et al., 2010). In contrast to Rab5-to-Rab7 conversion, little is known about how Rab5-to-Rab11 conversion along the recycling pathway is controlled. Krauss and Haucke, 2007). To confirm the localization of DRG2, we cotransfected MCF7 cells with DRG2 and markers for PIs, including Akt-PH for phosphatidylinositol (3,4,5)-trisphosphat...

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“…Two DRG2 Tg lines (45 and 50) were generated (18), and the genome DNA was extracted from the tail of the mice for genotyping by PCR. To generate DRG2 Tg mice, mouse DRG2 cDNA was placed downstream of the CMV promoter of pcDNA3.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of developmentally regulated GTP-binding protein-2 increases bone loss

Sul

Kim

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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The developmentally regulated GTP-binding protein-2 (DRG2) is a novel subclass of GTPbinding proteins. Many functional characteristics of osteoclasts (OC) are associated with small GTPases. We hypothesized that DRG2 affects bone mass via modulating OC activity. Using DRG2 transgenic mice, we investigated the role of DRG2 in bone remodeling. DRG2 overexpression caused a decrease in bone mass and an increase in the number and activity of OC in vivo. DRG2 overexpression increased fusion, spreading, survival, and resorption activity of OC in vitro. Downregulation of DRG2 by siRNA decreased fusion, spreading, and survival of OC, supporting the observations found in DRG2 transgenic OC. Transgenic mature OCs were larger, with actin rings and higher ERK, Akt, Rac1 and Rho activities than wild-type OCs. Inhibition of these proteins abolished the effects of DRG2 on formation of large OCs with actin rings, implying that DRG2 affects cytoskeleton reorganization in a Rac1/Rho/ERK/Akt-dependent manner. In summary, DRG2 is associated with survival and cytoskeleton organization of OC under influence of macrophage colony-stimulating factor, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss. DRG2; osteoclast; fusion; spreading; bone resorption BONE UNDERGOES DYNAMIC REMODELING, and maintenance of bone mass and integrity requires a precise balance between bone resorption by osteoclasts (OC) and bone formation by osteoblasts. In osteoporosis, resorption exceeds formation, whereas osteopetrosis is due to defective OC formation and function. OC differentiation depends on at least two factors derived from stromal cells/osteoblasts: macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-B ligand (RANKL) (3, 12). During differentiation, OCs become multinucleated by fusion, which plays a critical role in bone resorption (13). To actively resorb bone, OC forms an actin ring that is a complex molecular attachment structure that seals off an extracellular compartment located between the cell and resorbing bone (5). By virtue of tight sealing, the extracellular compartment is characterized by maintaining a low pH and enriching lysosomal enzymes that are required for digestion of the bone matrix.Many OC properties that are necessary for efficient bone resorption, such as actin ring formation, fusion, and cell survival, depend on the activity of small GTPases (6,15,16,36). The Rho family of GTPases plays a critical role in actin organization, with RhoA, Rac1, Cdc42, and RhoU being responsible for cytoskeletal organization and the polarization of OCs (6, 15, 36). The ARF GTPase family, known to regulate membrane trafficking and actin dynamics, is responsible for the regulation of the OC cytoskeleton and formation of the sealing zone (11). Decrease in Rac2 impairs migration and fusion required for OC and results in bone defects found in Shwachman-Diamond syndrome (24). The activity of Rac1 (9) and Ras (4) is essential for OC survival. Although several small GTPases have...

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Developmentally regulated GTP-binding protein 2 ameliorates EAE by suppressing the development of TH17 cells

Cited by 11 publications

References 31 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

Developmentally regulated GTP-binding protein 2 coordinates Rab5 activity and transferrin recycling

Overexpression of developmentally regulated GTP-binding protein-2 increases bone loss

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