ADP-ribosylation factor-like GTPase 15 enhances insulin-induced AKT phosphorylation in the IR/IRS1/AKT pathway by interacting with ASAP2 and regulating PDPK1 activity

Zhao, Jie; Wang, Min; Deng, Wuquan; Zhong, Dongdong; Jiang, Yao‐Guang; Liao, Yong; Chen, Bing; Zhang, Xiaoli

doi:10.1016/j.bbrc.2017.03.079

Cited by 22 publications

(25 citation statements)

References 29 publications

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“…Indeed, ARL15 has been associated with a wide range of metabolic parameters and diseases in GWAS, including adiponectin, HDL, diabetes mellitus and body shape[58][59][60][61][62][63].As these studies did not analyze Mg 2+ status as a modifying factor, it cannot be excluded that ARL15 has additional functions that explain these associations. Indeed, ARL15 has been demonstrated to modify the insulin-signaling pathway in myotubes[64].Overall, our work establishes complex N-glycosylation of CNNMs as an essential process to regulate their activity. This crucial post-translational modification promoted by ARL15 on CNNMs adds to recent mechanisms of CNNMs modulation such as their circadian rhythm expression…”

supporting

confidence: 51%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like protein 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

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supporting

confidence: 51%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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“…In fact, we found matching results from our study in adipose lineages with reported work done in other metabolic tissues. For instance, ARL15 and PEPD have been reported to promote cell proliferation with ARL15 in myotubes and skeletal muscles 46 , and PEPD in hepatocytes 47 . In contrast, silencing of ARL15 decreased the proliferation and glucose-stimulated insulin secretion of EndoC-β H1 cells 48 and in our study, knockout of ARL15 inhibited proliferation of preadipocyte and insulin-induced glucose uptake of adipocytes (Fig 6), consistent with existing evidence that GWAS loci and their effector genes can influence disease risk in a cell type-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Functional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes

Chen

Shi

et al. 2020

Circulation Research

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Rationale-Genome-wide association studies (GWAS) have identified genetic loci associated with insulin resistance (IR) but pinpointing the causal genes of a risk locus has been challenging. Objective-To identify candidate causal genes for IR, we screened regional and biologically plausible genes (16 in total) near the top ten IR-loci in risk-relevant cell types, namely preadipocytes and adipocytes. Methods and Results-We generated 16 human Simpson-Golabi-Behmel syndrome preadipocyte knockout lines (SGBS-KO) each with a single IR-gene knocked out by lentivirusmediated CRISPR/Cas9 system. We evaluated each gene knockout by screening IRrelevant phenotypes in the three insulin-sensitizing mechanisms, including adipogenesis, lipid metabolism and insulin signaling. We performed genetic analyses using data on the GTEx eQTL database and AMP T2D Knowledge Portal to evaluate whether candidate genes prioritized by our in vitro studies were eQTL genes in human subcutaneous adipose tissue (SAT), and whether expression of these genes is associated with risk of IR, type 2 diabetes (T2D) and cardiovascular diseases (CVD). We further validated the functions of three new adipose IR genes by overexpression-based phenotypic rescue in the SGBS-KO cell lines. Twelve genes, PPARG, IRS-1, FST, PEPD,

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“…Insulin resistance describes the need for increased insulin to achieve biological effects (40). The insulin signaling pathway is composed of various molecules and proteins which initiate IR tyrosine kinase activation and substrate phosphorylation (41). However, it is not known whether this pathway is affected by the altered expression of proteins and molecules, and the activation of enzymes and transcription factors in peripheral tissue induced by Tac.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of glucose metabolism associated genes in a tacrolimus‑induced post‑transplantation diabetes mellitus in rat model

Zhang

et al. 2019

Int J Mol Med

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Post-transplantation diabetes mellitus (PTdM) is a known side effect in transplant recipients administered with immunosuppressant drugs, such as tacrolimus (Tac). Although injury of islet cells is considered a major reason for Tac-induced PTdM, the involvement of insulin resistance in PTdM remains unknown. In the present study, expression levels of adipocytokines, glucose metabolism associated genes and peroxisome proliferator-activated receptor (PPAR)-γ in adipose, muscular and liver tissues from a rat model induced with Tac (1 mg/kg/day) were examined. Rats developed hyperglycemia and glucose intolerance after 10 days of Tac administration. A subgroup of diabetic rats was further treated with rosiglitazone (4 mg/kg), a PPAR-γ activator. Adipose, muscle and liver tissues were obtained on day 15 after induction and the results demonstrated that expression levels of adipocytokines, PPAR-γ and proteins in the insulin associated signaling pathway varied in the different groups. Rosiglitazone administration significantly improved hyperglycemia, glucose intolerance and expression levels of proteins associated with insulin signaling, as well as adipocytokines expression. The results of this study demonstrated that adipocytokines and PPAR-γ signaling may serve important roles in the pathogenesis of Tac-induced PTdM, which may provide a promising application in the treatment of PTdM in the future.

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ADP-ribosylation factor-like GTPase 15 enhances insulin-induced AKT phosphorylation in the IR/IRS1/AKT pathway by interacting with ASAP2 and regulating PDPK1 activity

Cited by 22 publications

References 29 publications

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Functional Screening of Candidate Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes

Altered expression of glucose metabolism associated genes in a tacrolimus‑induced post‑transplantation diabetes mellitus in rat model

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