The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes

Hall, Gentzon; Lane, Brandon; Khan, Kamal; Pediaditakis, Igor; Xiao, Jianqiu; Wu, Guanghong; Wang, Liming; Kovalik, Maria E; Chryst-Stangl, Megan; Davis, Erica E.; Spurney, Robert F.; Gbadegesin, Rasheed

doi:10.1681/asn.2017121338

Cited by 49 publications

(50 citation statements)

References 43 publications

(56 reference statements)

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“…Previous studies have suggested that PI3K and Rac have different downstream‐upstream linkages or that PI3K and Rac may be independent . In this study, we found that PPF and the subsequent platelet shedding triggered by MT primarily depended on the activation of PI3K‐Akt/Rac pathway.…”

Section: Discussionsupporting

confidence: 46%

“…Previous studies have suggested that PI3K and Rac have different downstream-upstream linkages or that PI3K and Rac may be independent. [42][43][44] In this study, we found that PPF and the subsequent platelet shedding triggered by MT primarily depended on the activation of PI3K-Akt/Rac pathway. Furthermore, we also found that both Akt and Rac act downstream of PI3K, Rac also served as a direct downstream target of PI3K.…”

Section: Discussionmentioning

confidence: 56%

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Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

Chen

Wang

et al. 2020

Journal of Pineal Research

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Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34+ and CD41+ cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation‐induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal‐regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3‐kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3‐phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1‐orchestrated activation of ERK1/2 and Akt signaling.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 56%

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

Chen

Wang

et al. 2020

Journal of Pineal Research

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“…8 Previous studies have found that ANLN can regulate actin cytoskeletal dynamics in podocytes. 9 Previous studies have also confirmed that ANLN expression is associated with prognosis in patients with breast, 10 bladder, 11 and colorectal cancers. 12 Pandi et al 13 confirmed that ANLN is a Wnt/β-catenin responsive gene in gastric cancer and can regulate the proliferation of gastric cancer cells.…”

Section: Introductionmentioning

confidence: 83%

Overexpression of ANLN in lung adenocarcinoma is associated with metastasis

Zheng

Yuan

et al. 2019

Thoracic Cancer

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Background ANLN has been identified as an actin‐binding protein and previous studies have suggested that ANLN is associated with actin cytoskeletal dynamics. Lung adenocarcinoma is a poor prognosis tumor. Metastasis is a very common complication and is regarded as the main cause for an unsatisfactory treatment outcome. Whether ANLN is involved in the metastasis of lung adenocarcinoma is unknown. Methods We performed immunohistochemical staining and analyzed the correlation between the expression level and pathological parameters. We tested the migration and invasion of A549 and PC9 cell after interference with ANLN expression by Transwell and scratch wound healing assays. Protein expression of E‐cadherin, vimentin and N‐cadherin were detected using Western blotting and immunofluorescence staining. The same experiment was also tested after overexpression of ANLN. Results The metastasis of patients with high expression of ANLN was significantly more than that of patients with low expression of ANLN. In vitro, after interfering with ANLN expression, E‐cadherin and vimentin expression were increased and N‐cadherin expression was decreased in A549 and PC9 cells. Migration and invasion ability of A549 and PC9 cells were decreased,vice versa. Conclusion Our study suggests that the expression of ANLN in lung adenocarcinoma is associated with metastasis of cancer cells. ANLN may be involved in the metastasis of lung adenocarcinoma by promoting epithelial mesenchymal transformation of tumor cells.

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“…Anillin has attracted increasing attention as a potential disease-related gene (ORPH:93213, OMIM:616027). Evidence point at anillin expression levels being associated with cell proliferation and migration disorders in cancer and kidney diseases [146][147][148][149] . Additional roles for this actin binding protein have been reported in nerve cell development 150,151 and dysregulation of Anillin has been implicated in central nervous system myelin disorders 152,153 .…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that anillin expression is positively associated with the expression of β-catenin (ctnnb1) 154 consistent with ctnnb1 also being an Atoh7-downregulated gene in our gene cohort. Furthermore, Anillin appears to be an essential regulator of epithelial cell-cell adherens junctions via regulation of the E-Cadherin/β-catenin complex 148,155,156 . In agreement with this idea, we here make the preliminary observation that anillin knock down results in accumulation and displacement of β-catenin signal in the apical and apical-lateral membrane of RPCs (Supp.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of the zebrafishatoh7−/−mutant,lakritz, highlights Atoh7-dependent genetic networks with potential implications for human eye diseases

Covello

Rossello

Filosi

et al. 2020

Preprint

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Short Running Title: Atoh7 genetic networks and human eye diseases. Nonstandard Abbreviations: RPCs: retinal progenitor cells NCRNA: retinal non-attachment ONH: optic nerve hypoplasia ONA: optic nerve aplasia PHPV: persistent hyperplastic primary vitreous RGCs: retinal ganglion cells EFTFs: eye field transcription factors ABSTRACT: Expression of the bHLH transcription protein Atoh7 is a crucial factor conferring competence to retinal progenitor cells for the development of retinal ganglion cells. A number of studies have emerged establishing ATOH7 as a retinal disease gene. Remarkably, such studies uncovered ATOH7 variants associated with global eye defects including optic nerve hypoplasia, microphthalmia, retinal vascular disorders and glaucoma. The complex genetic networks and cellular decisions arising downstream of atoh7 expression, and how their dysregulation cause development of such disease traits remains unknown. To begin to understand such Atoh7-dependent events in vivo we performed transcriptome analysis of wild type and atoh7 mutant (lakritz) zebrafish embryos at the onset of retinal ganglion cell differentiation. We investigated in silico interplays of atoh7 and other disease-related genes and pathways. By network reconstruction analysis of differentially expressed genes we identified gene clusters enriched in retinal development, cell cycle, chromatin remodelling, stress response and Wnt pathways. By weighted gene coexpression network we identified coexpression modules affected by the mutation and enriched in retina development genes tightly connected to atoh7. We established the groundwork whereby Atoh7-linked cellular and molecular processes can be investigated in the dynamic multitissue environment of the developing normal and diseased vertebrate eye. 3 KEY WORDS: Atoh7, Ath5, retinal ganglion cells, transcriptome analysis; inherited eye diseases; human retina; zebrafish 6 anesthetized for 5-10 min in Ethyl 3-aminobenzoate methanesulfonate (MS-222) (Sigma-Aldrich, Saint Louis, MO, USA) in E3 medium. The corresponding body of each embryo was collected and used immediately to perform genotyping analysis to identify the corresponding to lakritz and wild type eyes. All embryos were collected from the same batches of fish stock to maintain a uniform genetic background. DNA extraction from zebrafish body biopsies and genotyping Genomic DNA extraction from each single body was performed in 100 μl of lysis buffer containing Proteinase K-20mg/ml (EuroClone S.p.A. Milan, Italy), 2 M Tris-HCl ph 8.0, 0.5 M EDTA ph 8.0 and 5 M NaCl, 20 % SDS in a final volume of 50 μl ultra H20. After 3 hours of incubation at 65°C, the gDNA was purified with an Ethanol precipitation step and resuspended in 50 μl of Dnase/Rnase H2O. The genotyping was performed by Restriction Fragment Length Polymorphism (RFLP) assay as previously described 6 . An ∼ 300 bp fragment of atoh7 was PCR amplified with 1 U Taq DNA polymerase (Applied Biosystems by Life Technologies, Carlsbad, CA, USA) according to manufacturer protocols in a 30μl PC...

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The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes

Cited by 49 publications

References 43 publications

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

Overexpression of ANLN in lung adenocarcinoma is associated with metastasis

Transcriptome analysis of the zebrafishatoh7−/−mutant,lakritz, highlights Atoh7-dependent genetic networks with potential implications for human eye diseases

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