SHP2 knockdown ameliorates liver insulin resistance by activating IRS‐2 phosphorylation through the AKT and ERK1/2 signaling pathways

Yue, Xinxin; Han, Tao; Wu, Hao; Wang, Min; Fu, Yang

doi:10.1002/2211-5463.12992

Cited by 16 publications

(11 citation statements)

References 35 publications

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“… 85 Two other studies also reported that SHP2 promoted insulin resistance by regulating the insulin receptor substrate through Akt/ERK signaling pathways. 86 , 87 Liu et al also demonstrated that conditional knockout of SHP2 in macrophages or pharmacological inhibition of SHP2 ameliorated high-fat diet induced hepatic steatosis and insulin resistance by elevating IL-18 levels. 88 Therefore, SHP2 may be a strategic target for T2DM treatments.…”

Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 98%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

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Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 98%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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show abstract

“…The effects seen upon SHP2 (PTPN11) gene disruption (conditional knockout models) are variable and highly tissue dependent, probably due to the pleiotropic role of SHP2 in various growth factor pathways. Nevertheless, multiple experiments support that inhibition of SHP2 activity in the liver (but not in the skeletal muscle or pancreas) can ameliorate insulin resistance in mouse models 5 , 38 – 40 . In accordance with animal experiments, individuals with hereditary SHP2 gain-of-function mutations (Noonan syndrome) display insulin resistance more frequently than the generic population, despite their overall leaner phenotype 41 .…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling

et al. 2022

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Serine/threonine phosphorylation of insulin receptor substrate (IRS) proteins is well known to modulate insulin signaling. However, the molecular details of this process have mostly been elusive. While exploring the role of phosphoserines, we have detected a direct link between Tyr-flanking Ser/Thr phosphorylation sites and regulation of specific phosphotyrosine phosphatases. Here we present a concise structural study on how the activity of SHP2 phosphatase is controlled by an asymmetric, dual phosphorylation of its substrates. The structure of SHP2 has been determined with three different substrate peptides, unveiling the versatile and highly dynamic nature of substrate recruitment. What is more, the relatively stable pre-catalytic state of SHP2 could potentially be useful for inhibitor design. Our findings not only show an unusual dependence of SHP2 catalytic activity on Ser/Thr phosphorylation sites in IRS1 and CD28, but also suggest a negative regulatory mechanism that may also apply to other tyrosine kinase pathways as well.

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“…Glycolipid metabolism-related genes were IRS2, G6PC, MYC, SREBF1, GCK, FASN, HMGCR, CYP7A1, PLIN1, ELOVL6, and SCD2. IRS2, an important gene in the insulin signaling pathway, is closely related to the process of insulin resistance . G6PC is a rate-limiting enzyme in the gluconeogenesis and glycogenolysis, and the changes of its activity and expression directly affect the output of endogenous sugars .…”

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Revealed the Molecular Mechanism of miRNAs in Fluoride-Induced Hepatic Glucose and Lipid Metabolism Disorders

Zhao

Ommati

et al. 2022

J. Agric. Food Chem.

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Fluoride-induced liver injury seriously endangers human and animal health and animal food safety, but the underlying mechanism remains unclear. This study aims to explore the mechanism of miRNAs in fluoride-induced hepatic glycolipid metabolism disorders. C57 male mice were used to establish the fluorosis model ( 22.62 mg/L F − , 12 weeks). The results indicated that fluoride increased fluoride levels, impaired the structure and function, and disrupted the glycolipid metabolism in the liver. Furthermore, the sequencing results showed that fluoride exposure resulted in the differential expression of 35 miRNAs and 480 mRNAs, of which 23 miRNAs were related to glycolipid metabolism. miRNA−mRNA network analyses and RT-PCR revealed that miRNAs mediated fluoride-induced disturbances in the hepatic glycolipid metabolism. Its possible mechanism was to regulate the insulin pathway, PPAR pathway, and FOXO pathway, which in turn affected the bile secretion, the metabolic processes of glucose, the decomposition of lipids, and the synthesis of unsaturated fatty acids in the liver. This study provides a theoretical basis for miRNAs as diagnostic indicators and target drugs for the treatment of fluoride-induced liver injury.

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SHP2 knockdown ameliorates liver insulin resistance by activating IRS‐2 phosphorylation through the AKT and ERK1/2 signaling pathways

Abstract: Here, we report that SHP2 knockdown enhances glucose consumption, ameliorates insulin resistance, activates IRS‐2 and AKT, and inhibits ERK1/2 phosphorylation in liver.

Cited by 16 publications

References 35 publications

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling

Multiomics Analysis Revealed the Molecular Mechanism of miRNAs in Fluoride-Induced Hepatic Glucose and Lipid Metabolism Disorders

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