USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors

Bridges, Caitlin; Tan, Men Chee; Premarathne, Susitha; Nanayakkara, Devathri; Bellette, Bernadette; Zencak, Dusan; Domingo, Deepti; Gécz, Jozef; Murtaza, Mariyam; Jolly, Lachlan A.; Wood, Stephen A.

doi:10.1038/s41598-017-00149-0

Cited by 35 publications

(28 citation statements)

References 47 publications

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“…Signaling through mTORC1/S6K1, a downstream mTOR target, has been reported to act as a nutrient sensor that integrates a number of environmental signals (e.g., glucose and insulin) to contribute to the development of IR and obesity [27][28][29]. Decreased mTOR/S6K1 signaling has been shown to decrease or increase IR [29][30][31][32]. However, previous studies have reported conflicting results concerning the relationship between mTORC1 and IR.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, DOCK5-mediated regulation of the mTOR-S6K-IRS-1 pathway may represent a potential drug target for the pharmacological and genetic administration of DOCK5 to improve IR and metabolic disorders. mTORC1 contains Raptor and is sensitive to rapamycin [31,32]. Raptor is a specific and important component of mTORC1, which is a pivotal regulator for both metabolism and insulin sensitivity [30].…”

Section: Discussionmentioning

confidence: 99%

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DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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“…The embryonic neocortex is composed of multiple types of NPs and fate restricted neural cells. Therefore, to test the effect of Usp9x loss on Wnt target gene expression in a homogeneous NP population, USP9X was depleted in the human NP cell line, ReNcell VM, using doxycycline inducible shRNA against USP9X 29 . 72 hours after shRNA induction, USP9X protein was almost completely depleted in these cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ReNcell VM was obtained from Millipore (Darmstadt, Germany) and maintained according to the manufactures instructions. Doxycycline-inducible Usp9x knock-down ReNcell VMs were generated as described previously 29 , 68 .…”

Section: Methodsmentioning

confidence: 99%

Loss of Usp9x disrupts cell adhesion, and components of the Wnt and Notch signaling pathways in neural progenitors

Premarathne

Murtaza

Matigian

et al. 2017

Sci Rep

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Development of neural progenitors depends upon the coordination of appropriate intrinsic responses to extrinsic signalling pathways. Here we show the deubiquitylating enzyme, Usp9x regulates components of both intrinsic and extrinsic fate determinants. Nestin-cre mediated ablation of Usp9x from embryonic neural progenitors in vivo resulted in a transient disruption of cell adhesion and apical-basal polarity and, an increased number and ectopic localisation of intermediate neural progenitors. In contrast to other adhesion and polarity proteins, levels of β-catenin protein, especially S33/S37/T41 phospho-β-catenin, were markedly increased in Usp9x −/Y embryonic cortices. Loss of Usp9x altered composition of the β-catenin destruction complex possibly impeding degradation of S33/S37/T41 phospho-β-catenin. Pathway analysis of transcriptomic data identified Wnt signalling as significantly affected in Usp9x −/Y embryonic brains. Depletion of Usp9x in cultured human neural progenitors resulted in Wnt-reporter activation. Usp9x also regulated components of the Notch signalling pathway. Usp9x co-localized and associated with both Itch and Numb in embryonic neocortices. Loss of Usp9x led to decreased Itch and Numb levels, and a concomitant increase in levels of the Notch intracellular domain as well as, increased expression of the Notch target gene Hes5. Therefore Usp9x modulates and potentially coordinates multiple fate determinants in neural progenitors.

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“…As mentioned above, the "core" gene set also included factors of the chromatin-remodeling complex [41], such as Nipbl, Smarcc2, and Smarca4. Besides, Usp9X has been thought to be involved in developmental processes through Wnt/β-catenin and mTOR pathways [42]. These common pathways can cause shared symptoms among FXS, ID, and ASD.…”

Section: Overlap Among Fmrp Targets Neurogenesis Id and Asd-associamentioning

confidence: 99%

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/ß-catenin, and mTOR signaling during corticogenesis

Kikkawa

Inada

Sasaki

et al. 2020

Preprint

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Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the mouse cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 "core" genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/ß-catenin, and mTOR pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

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USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors

Cited by 35 publications

References 47 publications

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

Loss of Usp9x disrupts cell adhesion, and components of the Wnt and Notch signaling pathways in neural progenitors

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/ß-catenin, and mTOR signaling during corticogenesis

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