VEGFR-3 signaling is regulated by a G-protein activator, activator of G-protein signaling 8, in lymphatic endothelial cells

Sakima, Miho; Hayashi, Hisato; Mamun, Abdullah Al; Sato, Motohiko

doi:10.1016/j.yexcr.2018.04.007

Cited by 9 publications

(8 citation statements)

References 37 publications

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“…It has been described that FNDC1 regulates the androgen receptor in prostate cancer [3]. Furthermore, FNDC1 forms complexes with G protein beta gamma subunit and connexins in cardiomyocytes and regulates several VEGF receptors in endothelial cells [7, 8, 33]. FNDC4 has been shown to suppress inflammation via AMP-activated protein kinase (AMPK) phosphorylation and heme oxygenase-1 (HO-1) expression in adipocytes [34].…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer

Wuensch

Wizenty

Quint

et al. 2019

Gastroenterology Research and Practice

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Background. Fibronectin type III domain-containing (FNDC) proteins fulfill manifold functions in tissue development and regulation of cellular metabolism. FNDC4 was described as anti-inflammatory factor, upregulated in inflammatory bowel disease (IBD). FNDC signaling includes direct cell-cell interaction as well as release of bioactive peptides, like shown for FNDC4 or FNDC5. The G-protein-coupled receptor 116 (GPR116) was found as a putative FNDC4 receptor. We here aim to comprehensively analyze the mRNA expression of FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, and GPR116 in nonaffected and affected mucosal samples of patients with IBD or colorectal cancer (CRC). Methods. Mucosa samples were obtained from 30 patients undergoing diagnostic colonoscopy or from surgical resection of IBD or CRC. Gene expression was determined by quantitative real-time PCR. In addition, FNDC expression data from publicly available Gene Expression Omnibus (GEO) data sets (GDS4296, GDS4515, and GDS5232) were analyzed. Results. Basal mucosal expression revealed higher expression of FNDC3A and FNDC5 in the ileum compared to colonic segments. FNDC1 and FNDC4 were significantly upregulated in IBD. None of the investigated FNDCs was differentially expressed in CRC, just FNDC3A trended to be upregulated. The GEO data set analysis revealed significantly downregulated FNDC4 and upregulated GPR116 in microsatellite unstable (MSI) CRCs. The expression of FNDCs and GPR116 was independent of age and sex. Conclusions. FNDC1 and FNDC4 may play a relevant role in the pathobiology of IBD, but none of the investigated FNDCs is regulated in CRC. GPR116 may be upregulated in advanced or MSI CRC. Further studies should validate the altered FNDC expression results on protein levels and examine the corresponding functional consequences.

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Section: Discussionmentioning

confidence: 99%

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer

Wuensch

Wizenty

Quint

et al. 2019

Gastroenterology Research and Practice

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“…The effect of AGS8 knockdown on VEGFR-2 signal is associated with a decrease of cell surface expression of VEGFRs 15,16 . Therefore, we analyzed the cell surface expression of VEGFR-2 in RF/6A cells using FACS analysis with an FITC-conjugated anti-VEGFR-2 antibody.…”

Section: Resultsmentioning

confidence: 97%

“…Furthermore, AGS8-Gβγ formed a protein complex with VEGFR-2, suggesting a potential role for AGS8-Gβγ in VEGF signal processing during angiogenesis 15 . In addition, we recently demonstrated that AGS8 is also involved in the regulation of VEGFC-induced lymphangiogenesis through VEGFR-3 regulation in lymphatic endothelial cells 16 but is not involved in FGF- or EGF-induced cellular events 15,16 , suggesting that AGS8 is a specific VEGF signaling regulator.…”

Section: Introductionmentioning

confidence: 99%

Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization

Hayashi

Mamun

Takeyama

et al. 2019

Sci Rep

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Choroidal neovascularization (CNV) is associated with age-related macular degeneration (AMD), a major cause of vision loss among elderly people. Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets for the treatment of AMD. We recently reported that activator of G-protein signaling 8 (AGS8), a receptor-independent Gβγ regulator, is involved in VEGF-induced angiogenesis in cultured endothelial cells (EC); however, the role of AGS8 in CNV is not yet understood. This study aimed to explore the role of AGS8 in CNV in cultured cells, explanted choroid tissue, and laser-induced CNV in a mouse AMD model. AGS8 knockdown in cultured choroidal EC inhibited VEGF-induced VEGFR-2 phosphorylation, cell proliferation, and migration. AGS8 knockdown also downregulated cell sprouting from mouse choroidal tissue in ex vivo culture. A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo, demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. Together, these results demonstrate that AGS8 plays critical roles in VEGF-induced CNV.

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“…Vascular endothelial growth factor C (VEGFC) is a vascular epithelial growth factor. Its main function is to affect lymphatic epithelial cells together with its receptor VEGFR-3 (FLT4), thereby promoting cell growth and proliferation and regulating the growth of lymphatic vessels [38]. It has been reported that the interaction between VEGFC and VEGFR-3 mediates lymphatic endothelial cell (LEC) proliferation, survival, migration, and tube formation during the lymphangiogenesis process [39].…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Analysis of Chicken Cecum Tissues Following Eimeria tenella Infection in Vivo

Wang

Zou

et al. 2019

Genes

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Eimeria tenella (E. tenella) is one of the most frequent and pathogenic species of protozoan parasites of the genus Eimeria that exclusively occupies the cecum, exerting a high economic impact on the poultry industry. To investigate differentially expressed genes (DEGs) in the cecal tissue of Jinghai yellow chickens infected with E. tenella, the molecular response process, and the immune response mechanism during coccidial infection, RNA-seq was used to analyze the cecal tissues of an E. tenella infection group (JS) and an uninfected group (JC) on the seventh day post-infection. The DEGs were screened by functional and pathway enrichment analyses. The results indicated that there were 5477 DEGs (p-value < 0.05) between the JS and the JC groups, of which 2942 were upregulated, and 2535 were downregulated. GO analysis indicated that the top 30 significantly enriched GO terms mainly involved signal transduction, angiogenesis, inflammatory response, and blood vessel development. KEGG analysis revealed that the top significantly enriched signaling pathways included focal adhesion, extracellular matrix–receptor interaction, and peroxisome proliferator-activated receptor. The key DEGs in these pathways included ANGPTL4, ACSL5, VEGFC, MAPK10, and CD44. These genes play an important role in the infection of E. tenella. This study further enhances our understanding of the molecular mechanism of E. tenella infection in chickens.

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VEGFR-3 signaling is regulated by a G-protein activator, activator of G-protein signaling 8, in lymphatic endothelial cells

Cited by 9 publications

References 37 publications

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer

Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization

RNA Sequencing Analysis of Chicken Cecum Tissues Following Eimeria tenella Infection in Vivo

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