The Role of PTP1B O-GlcNAcylation in Hepatic  Insulin Resistance

Zhao, Yun; Tang, Zhuqi; Shen, Aiguo; Tao, Tao; Wan, Chunhua; Zhu, Xiaohui; Huang, Jieru; Zhang, Wanlu; Xia, Nana; Wang, Suxin; Cui, Shiwei; Zhang, Dongmei

doi:10.3390/ijms160922856

Cited by 27 publications

(25 citation statements)

References 33 publications

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“…The mechanism by which O-GlcNAc-inducing treatment inhibits IGF-1-induced PTP1B activity is unclear at the present time. A previous study showed that in liver cells, PTP1B could be O-GlcNAcylated by high glucose and/or by inhibition of OGA with PUGNAc, associated with decreased insulin-induced Akt phosphorylation 61 . However, we have evaluated the effect of TG + GlcN treatment on PTP1B O-GlcNAcylation and observed that no O-GlcNAc signal above background could be detected using RL2 antibody (Suppl.…”

Section: Discussionmentioning

confidence: 96%

Increased O-GlcNAcylation promotes IGF-1 receptor/PhosphatidyI Inositol-3 kinase/Akt pathway in cervical cancer cells

Jiménez-Castillo

Illescas-Barbosa

Zenteno

et al. 2022

Sci Rep

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O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post-translational modification on serine and threonine residues of cytosolic, nuclear and mitochondrial proteins. O-GlcNAcylation level is regulated by OGT (O-GlcNAc transferase), which adds GlcNAc on proteins, and OGA (O-GlcNAcase), which removes it. Abnormal level of protein O-GlcNAcylation has been observed in numerous cancer cell types, including cervical cancer cells. In the present study, we have evaluated the effect of increasing protein O-GlcNAcylation on cervical cancer-derived CaSki cells. We observed that pharmacological enhancement of protein O-GlcNAcylation by Thiamet G (an inhibitor of OGA) and glucosamine (which provides UDP-GlcNAc substrate to OGT) increases CaSki cells proliferation, migration and survival. Moreover, we showed that increased O-GlcNAcylation promotes IGF-1 receptor (IGF1R) autophosphorylation, possibly through inhibition of protein tyrosine-phosphatase 1B activity. This was associated with increased IGF-1-induced phosphatidyl-Inositol 3-phosphate production at the plasma membrane and increased Akt activation in CaSki cells. Finally, we showed that protein O-GlcNAcylation and Akt phosphorylation levels were higher in human cervical cancer samples compared to healthy cervix tissues, and a highly positive correlation was observed between O-GlcNAcylation level and Akt phosphorylation in theses tissues. Together, our results indicate that increased O-GlcNAcylation, by activating IGF1R/ Phosphatidyl inositol 3-Kinase (PI-3K)/Akt signaling, may participate in cervical cancer cell growth and proliferation.

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Section: Discussionmentioning

confidence: 96%

Increased O-GlcNAcylation promotes IGF-1 receptor/PhosphatidyI Inositol-3 kinase/Akt pathway in cervical cancer cells

Jiménez-Castillo

Illescas-Barbosa

Zenteno

et al. 2022

Sci Rep

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“…O-GlcNAcylation of protein tyrosine phosphatase 1B (PTP1B) at S104, S201, and S386 inhibits PTP1B activity, which leads to an increase in AKT and GSK3β activity and therefore insulin response in HepG2 cells. 120 Human small CTD phosphatase 1 (hSCP1) was identified as O-GlcNAc modified by Western blot, and its glycosite at S41 was confirmed by Q-TOF MS and site-directed mutagenesis. 121 Additionally, the phosphatase myosin phosphatase target subunit 1 (MYPT1) may regulate the substrate specificity of OGT.…”

Section: Phosphatasesmentioning

confidence: 99%

The O-GlcNAc Modification on Kinases

Schwein

Woo

2020

ACS Chem. Biol.

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O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in close proximity to protein sites that are likewise modified by phosphorylation. While several studies have uncovered crosstalk between these two signaling modifications on individual proteins and pathways, an understanding of the role of O-GlcNAc in regulating kinases, the enzymes that install the phosphate modification, is still emerging. Here we review recent methods to profile the O-GlcNAc modification on a global scale that have revealed over 100 kinases as modified by O-GlcNAc, and highlight existing studies about regulation of these kinases by O-GlcNAc. Continuing efforts to profile the O-GlcNAc proteome and understand the role of O-GlcNAc on kinases will reveal new mechanisms of regulation and potential avenues for manipulation of the signaling mechanisms at the intersection of O-GlcNAc and phosphorylation.

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“…Despite the fact that DC is associated with a state of insulin resistance, few studies have highlighted the effect of the HBP on insulin resistance. Whereas, O-GlcNAcylation of several insulin-signaling key players (such as AKT, PT1B, and PDK1) has been shown to be associated with insulin resistance in the liver ( 90 – 93 ), the effect of the HBP on insulin signaling in the heart has not been adequately addressed. Recently, we reported that FOXO1 was O-GlcNAcylated in the heart of lipodystrophic diabetic mice and that SGLT2i treatment reversed this increase ( 44 ).…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Chronic O-GlcNAcylation and Diabetic Cardiomyopathy: The Bitterness of Glucose

et al. 2018

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Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart.

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The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance

Cited by 27 publications

References 33 publications

Increased O-GlcNAcylation promotes IGF-1 receptor/PhosphatidyI Inositol-3 kinase/Akt pathway in cervical cancer cells

Increased O-GlcNAcylation promotes IGF-1 receptor/PhosphatidyI Inositol-3 kinase/Akt pathway in cervical cancer cells

The O-GlcNAc Modification on Kinases

Chronic O-GlcNAcylation and Diabetic Cardiomyopathy: The Bitterness of Glucose

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