Trafficking regulator of GLUT4-1 (TRARG1) is a GSK3 substrate

Duan, Xiaowen; Norris, Dougall M.; Humphrey, Sean J.; Yang, Pengyi; Cooke, Kristen C.; Bultitude, Will P.; Parker, B. L.; Conway, Olivia J.; Burchfield, James G.; Krycer, James R.; Brodsky, Frances M.; James, David E.; Fazakerley, Daniel J.

doi:10.1042/bcj20220153

Cited by 14 publications

(7 citation statements)

References 54 publications

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“…Following association of PI3K with IRS, this allows phosphorylation of its substrate to generate PtdIns (3,4,5)P3, which activates serine kinase AKT [26] . The activation of AKT results in insulin responses, including GLUT4 translocation to the membrane, increased glycogen synthesis after phosphorylation of GSK-3 [27][28][29] . In the liver of T2DM rats, reduced IRS-1, p-PI3K and p-AKT expressions were found, which were significantly increased after the treatment with 12.5 mg/kg WVBF treatment.…”

Section: Discussionmentioning

confidence: 99%

Veratrilla baillonii Franch alleviate the symptoms of diabetes in type 2 diabetic rats induced by high-fat diet and streptozotocin

Yan¹,

Zhang²,

Ma³

et al. 2024

Food Science and Human Wellness

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Our previous research studies have shown that Veratrilla baillonii Franch, a food supplement used by ethnic minorities in Southwest China, has multiple pharmacological activities, such as detoxifi cation, antiinfl ammatory, antioxidant, and anti-insulin resistance. However, the detailed signal pathways for its salutary effect on damages in multiple organs due to type 2 diabetes mellitus (T2DM) remains unclear. The current study is to evaluate the therapeutic effects of V. baillonii on T2DM rats and to explore the underlying mechanisms. The T2DM rat model was successfully established by a high-sugar and high-fat diet (HFD) combination with intraperitoneal injection of a small dose of streptozotocin (STZ, 35 mg/kg). Biochemical analysis and histopatholgical examinations were conducted to evaluate the anti-diabetic potential of water extracts of V. baillonii (WVBF). The results showed that the WVBF treatment can improve hyperglycemia and insulin resistance, ameliorate the liver, kidney and pancreas injuries via decreasing infl ammatory cytokines such as IL-6 and TNF-α, and oxidative damages. Further investigation suggested that WVBF modulates the signal transductions of the IRS1/PI3K/AKT/GLUT4 and AMPK pathways. These fi ndings demonstrate potentials of WVBF in the treatment of T2DM and possible mechanisms for its hepatoprotective activities.

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Section: Discussionmentioning

confidence: 99%

Veratrilla baillonii Franch alleviate the symptoms of diabetes in type 2 diabetic rats induced by high-fat diet and streptozotocin

Yan¹,

Zhang²,

Ma³

et al. 2024

Food Science and Human Wellness

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“…Therefore, it is expected that the response to insulin and megalin phosphorylation mediated by GSK3ß are affected in LS cellular models and, in general, cells with decreased function of OCRL1 would be less responsive to insulin. Moreover, in LS patients’ insulin signaling could be partially inhibited, affecting other processes including the stimulation of megalin expression under chronic kidney disease ( Hosojima et al, 2009 ; Bryniarski et al, 2018 ) and the insulin-mediated surface expression of GLUT4, a trafficking response that is inhibited by GSK3ß ( Duan X et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Participation of OCRL1, and APPL1, in the expression, proteolysis, phosphorylation and endosomal trafficking of megalin: Implications for Lowe Syndrome

Sandoval

Fuentealba²,

Marzolo³

2022

Front. Cell Dev. Biol.

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Megalin/LRP2 is the primary multiligand receptor for the re-absorption of low molecular weight proteins in the proximal renal tubule. Its function is significantly dependent on its endosomal trafficking. Megalin recycling from endosomal compartments is altered in an X-linked disease called Lowe Syndrome (LS), caused by mutations in the gene encoding for the phosphatidylinositol 5-phosphatase OCRL1. LS patients show increased low-molecular-weight proteins with reduced levels of megalin ectodomain in the urine and accumulation of the receptor in endosomal compartments of the proximal tubule cells. To gain insight into the deregulation of megalin in the LS condition, we silenced OCRL1 in different cell lines to evaluate megalin expression finding that it is post-transcriptionally regulated. As an indication of megalin proteolysis, we detect the ectodomain of the receptor in the culture media. Remarkably, in OCRL1 silenced cells, megalin ectodomain secretion appeared significantly reduced, according to the observation in the urine of LS patients. Besides, the silencing of APPL1, a Rab5 effector associated with OCRL1 in endocytic vesicles, also reduced the presence of megalin’s ectodomain in the culture media. In both silencing conditions, megalin cell surface levels were significantly decreased. Considering that GSK3ß-mediated megalin phosphorylation reduces receptor recycling, we determined that the endosomal distribution of megalin depends on its phosphorylation status and OCRL1 function. As a physiologic regulator of GSK3ß, we focused on insulin signaling that reduces kinase activity. Accordingly, megalin phosphorylation was significantly reduced by insulin in wild-type cells. Moreover, even though in cells with low activity of OCRL1 the insulin response was reduced, the phosphorylation of megalin was significantly decreased and the receptor at the cell surface increased, suggesting a protective role of insulin in a LS cellular model.

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“…, 2015 ). siRNA-mediated geneKD in 3T3-L1 adipocytes was performed as previously described ( Duan et al. , 2022 ).…”

Section: Methodsmentioning

confidence: 99%

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events

Neuhaus,

Fryklund,

Taylor

et al. 2023

MBoC

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Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.

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Trafficking regulator of GLUT4-1 (TRARG1) is a GSK3 substrate

Cited by 14 publications

References 54 publications

Veratrilla baillonii Franch alleviate the symptoms of diabetes in type 2 diabetic rats induced by high-fat diet and streptozotocin

Veratrilla baillonii Franch alleviate the symptoms of diabetes in type 2 diabetic rats induced by high-fat diet and streptozotocin

Participation of OCRL1, and APPL1, in the expression, proteolysis, phosphorylation and endosomal trafficking of megalin: Implications for Lowe Syndrome

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events

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