The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Liangyou Rui - One of the best experts on this subject based on the ideXlab platform.
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1760 p brain SH2B1 protects against obesity and insulin resistance through multiple hypothalamic neural circuits
Diabetes, 2020Co-Authors: Minhyun Kim, Lin Jiang, G Martin J R Myers, Liangyou RuiAbstract:SH2B1 is a SH2 and PH domain-containing adaptor protein and enhances signal transduction in response to leptin, insulin, brain-derived neurotrophic factor (BDNF), and other ligands. Leptin, insulin and BDNF are known to activate the hypothalamic neural circuitry that controls energy balance, body weight, and metabolism. Genome-wide studies have identified numerous SH2B1 single nucleotide polymorphisms linked to human obesity and diabetes. SH2B1 nonsense and missense mutations have also been reported to be associated with obesity and type 2 diabetes in humans. We previously reported that global deletion of SH2B1 results in hyperphagia, obesity, and type 2 diabetes in mice. Here, we attempted to identify SH2B1 target cells, using conditional SH2B1 knockout mice. We ablated SH2B1 in the ventromedial hypothalamus (VMH) of SH2B1flox/flox mice (SH2B1ΔVMH) either by transducing the VMH with AAV-Cre vectors or using Sf1-Cre drivers. Both SH2B1ΔVMH males and females, like global SH2B1 knockout mice, developed obesity, insulin resistance, and liver steatosis. To further map SH2B1 neurons, we generated leptin receptor (LepR) neuron-specific SH2B1 knockout (SH2B1ΔLepR) mice using LepR-Cre drivers. SH2B1ΔLepR males and females also developed obesity, insulin resistance, glucose intolerance, and liver steatosis. Brown adipose tissue (BAT) thermogenic programs were severely impaired in SH2B1ΔLepR mice, leading to decreased core body temperature and cold intolerance. Remarkably, SH2B1 deficiency completely abrogated the ability of leptin to stimulate sympathetic nerves projecting to BAT in SH2B1ΔLepR mice, indicating that SH2B1 mediates leptin actions on sympathetic-controlled energy expenditure and metabolism. Collectively, our data suggest that hypothalamic SH2B1 influences multiple neural circuits controlling food intake, energy expenditure, and metabolic processes by integrating leptin, insulin, BDNF, and/or other nutritional signals. Disclosure Y. Li: None. M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.
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leptin receptor expressing neuron SH2B1 supports sympathetic nervous system and protects against obesity and metabolic disease
Nature Communications, 2020Co-Authors: Lin Jiang, Hong Shen, Minhyun Kim, Martin G Myers, Chung Owyang, Liangyou RuiAbstract:Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover SH2B1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of SH2B1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of SH2B1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of SH2B1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron SH2B1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.
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4e bp2 SH2B1 irs2 are part of a novel feedback loop that controls β cell mass
Diabetes, 2016Co-Authors: Manuel Blandinorosano, Liangyou Rui, Joshua O Scheys, Margarita Jimenezpalomares, Rebecca Barbaresso, Aaron Bender, Akiko Yanagiya, Ming Liu, Nahum Sonenberg, Ernesto BernalmizrachiAbstract:The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and β-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and β-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of β-cells.
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SH2B1 regulation of energy balance, body weight, and glucose metabolism.
World journal of diabetes, 2014Co-Authors: Liangyou RuiAbstract:The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuron-specific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans.
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SH2B1 in β cells promotes insulin expression and glucose metabolism in mice
Molecular Endocrinology, 2014Co-Authors: Zheng Chen, Lin Jiang, David Morris, Yong 刘勇 Liu, Liangyou RuiAbstract:Insulin deficiency drives the progression of both type 1 and type 2 diabetes. Pancreatic β-cell insulin expression and secretion are tightly regulated by nutrients and hormones; however, intracellular signaling proteins that mediate nutrient and hormonal regulation of insulin synthesis and secretion are not fully understood. SH2B1 is an SH2 domain-containing adaptor protein. It enhances the activation of the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription and the phosphatidylinositol 3-kinase pathways in response to a verity of hormones, growth factors, and cytokines. Here we identify SH2B1 as a new regulator of insulin expression. In rat INS-1 832/13 β-cells, SH2B1 knockdown decreased, whereas SH2B1 overexpression increased, both insulin expression and glucose-stimulated insulin secretion. SH2B1-deficent islets also had reduced insulin expression, insulin content, and glucose-stimulated insulin secretion. Heterozygous deletion of SH2B1 decreased pancreatic insulin content ...
Linyi Chen - One of the best experts on this subject based on the ideXlab platform.
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SH2B1 modulates chromatin state and myod occupancy to enhance expressions of myogenic genes
Biochimica et Biophysica Acta, 2017Co-Authors: Kuanwei Chen, Yu-jung Chang, Yenling Lian, Michael W Y Chan, Linyi ChenAbstract:Abstract As mesoderm-derived cell lineage commits to myogenesis, a spectrum of signaling molecules, including insulin growth factor (IGF), activate signaling pathways and ultimately instruct chromatin remodeling and the transcription of myogenic genes. MyoD is a key transcription factor during myogenesis. In this study, we have identified and characterized a novel myogenic regulator, SH2B1. Knocking down SH2B1 delays global chromatin condensation and decreases the formation of myotubes. SH2B1 interacts with histone H1 and is required for the removal of histone H1 from active transcription sites, allowing for the expressions of myogenic genes, IGF2 and MYOG . Chromatin immunoprecipitation assays suggest the requirement of SH2B1 for the induction of histone H3 lysine 4 trimethylation as well as the reduction of histone H3 lysine 9 trimethylation at the promoters and/or enhancers of IGF2 and MYOG genes during myogenesis. Furthermore, SH2B1 is required for the transcriptional activity of MyoD and MyoD occupancy at the enhancer/promoter regions of IGF2 and MYOG during myogenesis. Together, this study demonstrates that SH2B1 fine-tunes global-local chromatin states, expressions of myogenic genes and ultimately promotes myogenesis.
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SH2B1 orchestrates signaling events to filopodium formation during neurite outgrowth
Communicative & integrative biology, 2015Co-Authors: Kuanwei Chen, Yu-jung Chang, Linyi ChenAbstract:Morphogenesis during development is fundamental to the differentiation of several cell types. As neurite outgrowth marks neuritogenesis, formation of filopodia precede the formation of dendrites and axons. While the structure of filopodia is well-known, the initiation of filopodia during neurite outgrowth is not clear. SH2B1 is known to promote neurite outgrowth of PC12 cells, hippocampal and cortical neurons. As a signaling adaptor protein, SH2B1 interacts with several neurotrophin receptors, and regulates signaling as well as gene expression. Our recent findings suggest that SH2B1 can be recruited to the plasma membrane and F-actin fractions by IRSp53. IRSp53 bends plasma membrane and facilitates actin bundling to set the stage for filopodium formation. We further demonstrate that SH2B1-IRSp53 complexes enhance the formation of filopodia, dendrites and dendritic branches of hippocampal and cortical neurons. While the molecular mechanism underlying filopodium initiation is not clear, we propose that SH2B1-neurotrophin interacting sites may mark the putative sites of filopodium initiation.
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SH2B1 and IRSp53 proteins promote the formation of dendrites and dendritic branches.
The Journal of biological chemistry, 2015Co-Authors: Chien-jen Chen, Yu-jung Chang, Shao-jing Hong, Chien-hung Shih, Lily Hui-ching Wang, Linyi ChenAbstract:SH2B1 is an adaptor protein known to enhance neurite outgrowth. In this study, we provide evidence suggesting that the SH2B1 level is increased during in vitro culture of hippocampal neurons, and the β isoform (SH2B1β) is the predominant isoform. The fact that formation of filopodia is prerequisite for neurite initiation suggests that SH2B1 may regulate filopodium formation and thus neurite initiation. To investigate whether SH2B1 may regulate filopodium formation, the effect of SH2B1 and a membrane and actin regulator, IRSp53 (insulin receptor tyrosine kinase substrate p53), is investigated. Overexpressing both SH2B1β and IRSp53 significantly enhances filopodium formation, neurite outgrowth, and branching. Both in vivo and in vitro data show that SH2B1 interacts with IRSp53 in hippocampal neurons. This interaction depends on the N-terminal proline-rich domains of SH2B1. In addition, SH2B1 and IRSp53 co-localize at the plasma membrane, and their levels increase in the Triton X-100-insoluble fraction of developing neurons. These findings suggest that SH2B1-IRSp53 complexes promote the formation of filopodia, neurite initiation, and neuronal branching.
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SH2B1 increases the numbers of IRSp53-induced filopodia
Biochimica et biophysica acta, 2014Co-Authors: Shao-jing Hong, Szu-ting Liu, Chien-jen Chen, Linyi ChenAbstract:Abstract Background Filopodia are actin-rich membrane protrusions that play instrumental roles in development, cell migration, pathogen detection, and wound healing. During neurogenesis, filopodium formation precedes the formation of dendrites and spines. The insulin receptor substrate protein of 53 kDa (IRSp53) has been implicated in regulating the formation of filopodia. Our previous results suggest that a signaling adaptor protein SH2B1β is required for neurite outgrowth of hippocampal neurons and neurite initiation of PC12 cells. Thus, we hypothesize that IRSp53 and SH2B1β may act together to regulate filopodium formation. Methods To determine the contribution of IRSp53 and SH2B1β in the formation of filopodia, we transiently transfect IRSp53 and/or SH2B1β to 293T cells. Cell morphology and protein distribution are assessed via confocal microscopy and subcellular fractionation. Total numbers of filopodia and filopodium numbers per perimeter are calculated to show the relative contribution of IRSp53 and SH2B1β. Results In this study, we show that SH2B1β interacts with IRSp53 and increases the number of IRSp53-induced filopodia. One mechanism for this enhancement is that IRSp53 recruits SH2B1β to the plasma membrane to actively promote membrane protrusion. The increased numbers of filopodia likely result from SH2B1-mediated cytoplasmic extension and thus increased cell perimeter as well as IRSp53-mediated filopodium formation. Conclusions Taken together, this study provides a novel finding that SH2B1β interacts with IRSp53-containing complexes to increase the number of filopodia. General significance A better understanding of how SH2B1β and IRSp53 promote filopodium formation may have clinical implication in neurogenesis and regeneration.
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signaling adaptor protein SH2B1 enhances neurite outgrowth and accelerates the maturation of human induced neurons
Stem Cells Translational Medicine, 2014Co-Authors: Yichao Hsu, Linyi Chen, Suliang Chen, Yajean Wang, Yunhsiang Chen, Danyen Wang, Chiahsiang Chen, Hweihsien Chen, Ingming ChiuAbstract:Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibited action potentials as early as day 14; without SH2B1, the IBM iNs do not exhibit action potentials until day 21. Our data demonstrate that SH2B1 can enhance neurite outgrowth and accelerate the maturation of human iNs under defined conditions. This approach will facilitate the application of iNs in regenerative medicine and in vitro disease modeling.
Chunfang Zhang - One of the best experts on this subject based on the ideXlab platform.
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new perspective on SH2B1 an accelerator of cancer progression
Biomedicine & Pharmacotherapy, 2020Co-Authors: Yuanda Cheng, Chaojun Duan, Chunfang ZhangAbstract:SH2B1 is well-known as an adaptor protein, and deletion of SH2B1 results in severe obesity and both leptin and insulin resistance. Some studies have revealed that SH2B1 is involved in the progression of lung cancer, esophageal cancer, gastric cancer, oropharyngeal cancer, and so on. Biological function experiments have proven that SH2B1 can regulate cellular morphology, motility and adhesion by modifying the actin cytoskeletal reorganization, and it can promote cell mitogenesis, transformation, survival and differentiation via different signal pathways by enhancing the kinase activity of several receptor tyrosine kinases. In addition, SH2B1 is an obesity-related gene, and epidemiological surveys suggest a complex relationship between obesity and cancer. Therefore, what is the relationship between SH2B1 and cancer? Herein, we attempt to provide a mini overview of the roles of SH2B1 in cancer.
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SH2B1 promotes nsclc cell proliferation through pi3k akt mtor signaling cascade
Cancer Cell International, 2018Co-Authors: Shaoqiang Wang, Yuanda Cheng, Wolong Zhou, Yingying Zheng, Chunfang ZhangAbstract:Non-small cell lung cancer (NSCLC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers. The objective of this study was to investigate the role SH2B1 and the underlying molecular mechanism in NSCLC. Cell functional analysis and cell line-derived xenograft model were performed to determine SH2B1 potential roles on NSCLC cell proliferation in vitro and in vivo. In vitro assays were performed to identify signal molecular mechanisms. Subsequently, 104 patients with NSCLC undergoing primary surgical resection were recruited to evaluated expression of SH2B1 and Akt/mTOR signaling markers by immunohistochemical staining to determine their clinicopathologic significance. Modulation of SH2B1 expression levels had distinct effects on cell proliferation, cell cycle and apoptosis in the NSCLC cell lines A549 and H1299. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the Akt/mTOR markers, p-Akt and p-mTOR, and downregulation of PTEN to promote NSCLC cell proliferation, while silencing SH2B1 had the opposite effect. In human NSCLC specimens, SH2B1 expression levels were positively associated with Akt/mTOR signaling pathway markers. The SH2B1/Akt/mTOR/PTEN axis is required for regulating NSCLC cell proliferation and might prove to be a promising strategy for restraining tumor progression in NSCLC patients.
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SH2B1 promotes epithelial mesenchymal transition through the irs1 β catenin signaling axis in lung adenocarcinoma
Molecular Carcinogenesis, 2018Co-Authors: Shaoqiang Wang, Yuanda Cheng, Chaojun Duan, Yang Gao, Wolong Zhou, Ruimin Chang, Zhenzi Peng, Yingying Zheng, Chunfang ZhangAbstract:Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced β-catenin accumulation and activated β-catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1-IRS1-β-catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.
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microrna 361 3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in nsclc
Journal of Experimental & Clinical Cancer Research, 2016Co-Authors: Wei Chen, Yuanda Cheng, Chaojun Duan, Shaoqiang Wang, Wolong Zhou, Jun Wang, Sulai Liu, Chunfang ZhangAbstract:Lung cancer is the most common malignancies worldwide. However, the detailed molecular mechanisms underlying lung cancer progression are still not completely clear. MicroRNAs are small noncoding RNAs which occupy a crucial role of cancer metastasis. Accumulating evidence suggests that miR-361 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive, especially in lung cancer. This study examined the role of miR-361-3p in non-small cell lung cancer (NSCLC). Real-time quantitative PCR (qRT-PCR) was used to analyze the expression of miR-361-3p in NSCLC tissue and in compared adjacent non-cancerous tissues. The effect of miR-361-3p on proliferation was evaluated by CCK8 and colony formation assays. The effect of miR-361-3p on migration and invasion was evaluated by transwell assays. Western blotting and immunohistochemical staining were applied to analyze the expression of target proteins and downstream molecule, and the luciferase reporter assay to assess the target genes of miR-361-3p in non-small cell lung cancer cells. miR-361-3p was significantly decreased in NSCLC tissue and cell lines, and its expression levels were highly correlated with lymph node metastasis (P < 0.01) and TNM stages (P < 0.05). Down-regulation of miR-361-3p promoted cell growth, proliferation, colony formation, invasion and migration in vitro, and promoted proliferation and metastasis in vivo (P < 0.01); whereas up-regulation of miR-361-3p had the contrary effects. The luciferase reporter assay showed that SH2B1 was a direct target gene of miR-361-3p. Enforced expression of miR-361-3p inhibited the expression of SH2B1 significantly and the restoration of SH2B1 expression reversed the inhibitory effects of miR-361-3p on NSCLC cell proliferation and metastasis. miR-361-3p functions as a novel tumor suppressor in NSCLC and the anti-oncogenic activity may involve its inhibition of the target gene SH2B1. These findings suggest the possibility for miR-361-3p as a therapeutic target in NSCLC.
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expression of SH2B1 adaptor protein in oesophageal cancer and its clinical significance
Journal of Central South University. Medical sciences, 2013Co-Authors: Huiqiong Zhang, Yuanda Cheng, Chaojun Duan, Chunfang ZhangAbstract:Objective: To explore the expression of SH2B1 adaptor protein in oesophageal cancer and its clinical significance.Methods: SH2B1 expression in tissue specimens of 120 primary oesophageal cancers,tissues of 120 paired adjacent non-cancer and another 120 normal tissues was analyzed by immunohistochemical SABC staining and Western blot.SH2B1 expression in the oesophageal cancer tissues was analyzed with clinicopathological parameters.SH2B1 expression of normal human esophageal epithelial cells(HEEC) and 2 oesophageal cancer cell lines,TE-1 and Eca109,were evaluated by RT-PCR and Western blot.Results: SH2B1 expression in the normal oesophageal tissues,adjacent non-cancer tissues and cancer tissues was gradually increased(P0.05),and significantly associated with the depth of invasion,clinical TNM stage,lymph node metastasis(P0.05),but it did not have significant association with gender,age,drinking,type and grade of tumor(P0.05).SH2B1 expression was detectable in all cell lines by RT-PCR and Western blot,but the expression in the two oesophageal cancer cell lines was significantly higher than that in the normal HEEC.Conclusions: Over-expression of SH2B1 might play an important role in the occurrence and development of human oesophageal cancer and closely correlate with malignant progression of invasion and metastasis of oesophageal cancer.
Christin Cartersu - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of the unique c terminal tail of the alpha isoform of the scaffold protein SH2B1 controls the ability of SH2B1α to enhance nerve growth factor function
Molecular and Cellular Biology, 2017Co-Authors: Ray M Joe, Anabel Flores, Lawrence S Argetsinger, Paul B Vander, Joel M Cline, Michael E Doche, Erik S Clutter, Heimo Riedel, Christin CartersuAbstract:The scaffold protein SH2B1, a major regulator of body weight, is recruited to the receptors of multiple cytokines and growth factors, including nerve growth factor (NGF). The β isoform but not the α isoform of SH2B1 greatly enhances NGF-dependent neurite outgrowth of PC12 cells. Here, we asked how the unique C-terminal tails of the α and β isoforms modulate SH2B1 function. We compared the actions of SH2B1α and SH2B1β to those of the N-terminal 631 amino acids shared by both isoforms. In contrast to the β tail, the α tail inhibited the ability of SH2B1 to both cycle through the nucleus and enhance NGF-mediated neurite outgrowth, gene expression, phosphorylation of Akt and phospholipase C-gamma (PLC-γ), and autophosphorylation of the NGF receptor TrkA. These functions were restored when Tyr753 in the α tail was mutated to phenylalanine. We provide evidence that TrkA phosphorylates Tyr753 in SH2B1α, as well as tyrosines 439 and 55 in both SH2B1α and SH2B1β. Finally, coexpression of SH2B1α but not SH2B1α with a mutation of Y to F at position 753 (Y753F) inhibited the ability of SH2B1β to enhance neurite outgrowth. These results suggest that the C-terminal tails of SH2B1 isoforms are key determinants of the cellular role of SH2B1. Furthermore, the function of SH2B1α is regulated by phosphorylation of the α tail.
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the SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor
Journal of Biological Chemistry, 2012Co-Authors: Mojib Javadi, Christin Cartersu, Edda Hofstatter, Natalie Stickle, Bryan K Beattie, Robert Jaster, Dwayne L BarberAbstract:Gene targeting experiments have shown that the cytokine erythropoietin (EPO), its cognate erythropoietin receptor (EPO-R), and associated Janus tyrosine kinase, JAK2, are all essential for erythropoiesis. Structural-functional and murine knock-in experiments have suggested that EPO-R Tyr-343 is important in EPO-mediated mitogenesis. Although Stat5 binds to EPO-R phosphotyrosine 343, the initial Stat5-deficient mice did not have profound erythroid abnormalities suggesting that additional Src homology 2 (SH2) domain-containing effectors may bind to EPO-R Tyr-343 and couple to downstream signaling pathways. We have utilized cloning of ligand target (COLT) screening to demonstrate that EPO-R Tyr(P)-343 and Tyr(P)-401 bind to the SH2 domain-containing adaptor protein SH2B1β. Immunoprecipitation and in vitro mixing experiments reveal that EPO-R binds to SH2B1 in an SH2 domain-dependent manner and that the sequence that confers SH2B1 binding to the EPO-R is pYXXL. Previous studies have shown that SH2B1 binds directly to JAK2, but we show that in hematopoietic cells, SH2B1β preferentially associates with the EPO-R. SH2B1 is capable of constitutive association with EPO-R, which is necessary for its optimal SH2-dependent recruitment to EPO-R-Tyr(P)-343/Tyr(P)-401. We also demonstrate that SH2B1 is responsive to EPO stimulation and becomes phosphorylated, most likely on serines/threonines, in an EPO dose- and time-dependent manner. In the absence of SH2B1, we observe enhanced activation of signaling pathways downstream of the EPO-R, indicating that SH2B1 is a negative regulator of EPO signaling.
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nucleocytoplasmic shuttling of the adapter protein SH2B1β sh2 bβ is required for nerve growth factor ngf dependent neurite outgrowth and enhancement of expression of a subset of ngf responsive genes
Molecular Endocrinology, 2009Co-Authors: Travis J. Maures, Linyi Chen, Christin CartersuAbstract:The adapter protein SH2B1 (SH2-B, PSM) is recruited to multiple ligand-activated receptor tyrosine kinases, including the receptors for nerve growth factor (NGF), insulin, and IGF-I as well as the cytokine receptor-associated Janus kinase family kinases. In this study, we examine SH2B1's function in NGF signaling. We show that depleting endogenous SH2B1 using short hairpin RNA against SH2B1 inhibits NGF-dependent neurite outgrowth, but not NGF-mediated phosphorylation of Akt or ERKs 1/2. SH2B1 has been hypothesized to localize and function at the plasma membrane. We identify a nuclear localization signal within SH2B1 and show that it is required for nuclear translocation of SH2B1beta. Mutation of the nuclear localization signal has no effect on NGF-induced activation of TrkA and ERKs 1/2 but prevents SH2B1beta from enhancing NGF-induced neurite outgrowth. Disruption of SH2B1beta nuclear import also prevents SH2B1beta from enhancing NGF-induced transcription of genes important for neuronal differentiation, including those encoding urokinase plasminogen activator receptor, and matrix metalloproteinases 3 and 10. Disruption of SH2B1beta nuclear export by mutation of its nuclear export sequence similarly prevents SH2B1beta enhancement of NGF-induced transcription of those genes. Nuclear translocation of the highly homologous family member SH2B2(APS) was not observed. Together, these data suggest that rather than simply acting as an adapter protein linking signaling proteins to the activated TrkA receptor at the plasma membrane, SH2B1beta must shuttle between the plasma membrane and nucleus to function as a critical component of NGF-induced gene expression and neuronal differentiation.
Lin Jiang - One of the best experts on this subject based on the ideXlab platform.
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1760 p brain SH2B1 protects against obesity and insulin resistance through multiple hypothalamic neural circuits
Diabetes, 2020Co-Authors: Minhyun Kim, Lin Jiang, G Martin J R Myers, Liangyou RuiAbstract:SH2B1 is a SH2 and PH domain-containing adaptor protein and enhances signal transduction in response to leptin, insulin, brain-derived neurotrophic factor (BDNF), and other ligands. Leptin, insulin and BDNF are known to activate the hypothalamic neural circuitry that controls energy balance, body weight, and metabolism. Genome-wide studies have identified numerous SH2B1 single nucleotide polymorphisms linked to human obesity and diabetes. SH2B1 nonsense and missense mutations have also been reported to be associated with obesity and type 2 diabetes in humans. We previously reported that global deletion of SH2B1 results in hyperphagia, obesity, and type 2 diabetes in mice. Here, we attempted to identify SH2B1 target cells, using conditional SH2B1 knockout mice. We ablated SH2B1 in the ventromedial hypothalamus (VMH) of SH2B1flox/flox mice (SH2B1ΔVMH) either by transducing the VMH with AAV-Cre vectors or using Sf1-Cre drivers. Both SH2B1ΔVMH males and females, like global SH2B1 knockout mice, developed obesity, insulin resistance, and liver steatosis. To further map SH2B1 neurons, we generated leptin receptor (LepR) neuron-specific SH2B1 knockout (SH2B1ΔLepR) mice using LepR-Cre drivers. SH2B1ΔLepR males and females also developed obesity, insulin resistance, glucose intolerance, and liver steatosis. Brown adipose tissue (BAT) thermogenic programs were severely impaired in SH2B1ΔLepR mice, leading to decreased core body temperature and cold intolerance. Remarkably, SH2B1 deficiency completely abrogated the ability of leptin to stimulate sympathetic nerves projecting to BAT in SH2B1ΔLepR mice, indicating that SH2B1 mediates leptin actions on sympathetic-controlled energy expenditure and metabolism. Collectively, our data suggest that hypothalamic SH2B1 influences multiple neural circuits controlling food intake, energy expenditure, and metabolic processes by integrating leptin, insulin, BDNF, and/or other nutritional signals. Disclosure Y. Li: None. M. Kim: None. L. Jiang: None. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc. L. Rui: None.
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leptin receptor expressing neuron SH2B1 supports sympathetic nervous system and protects against obesity and metabolic disease
Nature Communications, 2020Co-Authors: Lin Jiang, Hong Shen, Minhyun Kim, Martin G Myers, Chung Owyang, Liangyou RuiAbstract:Leptin stimulates the sympathetic nervous system (SNS), energy expenditure, and weight loss; however, the underlying molecular mechanism remains elusive. Here, we uncover SH2B1 in leptin receptor (LepR) neurons as a critical component of a SNS/brown adipose tissue (BAT)/thermogenesis axis. LepR neuron-specific deletion of SH2B1 abrogates leptin-stimulated sympathetic nerve activation and impairs BAT thermogenic programs, leading to reduced core body temperature and cold intolerance. The adipose SNS degenerates progressively in mutant mice after 8 weeks of age. Adult-onset ablation of SH2B1 in the mediobasal hypothalamus also impairs the SNS/BAT/thermogenesis axis; conversely, hypothalamic overexpression of human SH2B1 has the opposite effects. Mice with either LepR neuron-specific or adult-onset, hypothalamus-specific ablation of SH2B1 develop obesity, insulin resistance, and liver steatosis. In contrast, hypothalamic overexpression of SH2B1 protects against high fat diet-induced obesity and metabolic syndromes. Our results unravel an unrecognized LepR neuron SH2B1/SNS/BAT/thermogenesis axis that combats obesity and metabolic disease.
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neural deletion of SH2B1 results in brain growth retardation and reactive aggression
The FASEB Journal, 2017Co-Authors: Lin Jiang, Julia M Keogh, Elana Henning, Zheng Chen, Paul Wilkinson, Ian Goodyer, Sadaf I FarooqiAbstract:Psychiatric disorders are associated with aberrant brain development and/or aggressive behavior and are influenced by genetic factors; however, genes that affect brain aggression circuits remain elusive. Here, we show that neuronal Src-homology-2 (SH2)B adaptor protein-1 ( SH2B1) is indispensable for both brain growth and protection against aggression. Global and brain-specific deletion of SH2B1 decreased brain weight and increased aggressive behavior. Global and brain-specific SH2B1 knockout (KO) mice exhibited fatal, intermale aggression. In a resident-intruder paradigm, latency to attack was markedly reduced, whereas the number and the duration of attacks was significantly increased in global and brain-specific SH2B1 KO mice compared with wild-type littermates. Consistently, core aggression circuits were activated to a higher level in global and brain-specific SH2B1 KO males, based on c-fos immunoreactivity in the amygdala and periaqueductal gray. Brain-specific restoration of SH2B1 normalized brain size and reversed pathologic aggression and aberrant activation of core aggression circuits in SH2B1 KO males. SH2B1 mutations in humans were linked to aberrant brain development and behavior. At the molecular level, SH2B1 enhanced neurotrophin-stimulated neuronal differentiation and protected against oxidative stress-induced neuronal death. Our data suggest that neuronal SH2B1 promotes brain development and the integrity of core aggression circuits, likely through enhancing neurotrophin signaling.-Jiang, L., Su, H., Keogh, J. M., Chen, Z., Henning, E., Wilkinson, P., Goodyer, I., Farooqi, I. S., Rui, L. Neural deletion of SH2B1 results in brain growth retardation and reactive aggression.
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SH2B1 in β cells promotes insulin expression and glucose metabolism in mice
Molecular Endocrinology, 2014Co-Authors: Zheng Chen, Lin Jiang, David Morris, Yong 刘勇 Liu, Liangyou RuiAbstract:Insulin deficiency drives the progression of both type 1 and type 2 diabetes. Pancreatic β-cell insulin expression and secretion are tightly regulated by nutrients and hormones; however, intracellular signaling proteins that mediate nutrient and hormonal regulation of insulin synthesis and secretion are not fully understood. SH2B1 is an SH2 domain-containing adaptor protein. It enhances the activation of the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription and the phosphatidylinositol 3-kinase pathways in response to a verity of hormones, growth factors, and cytokines. Here we identify SH2B1 as a new regulator of insulin expression. In rat INS-1 832/13 β-cells, SH2B1 knockdown decreased, whereas SH2B1 overexpression increased, both insulin expression and glucose-stimulated insulin secretion. SH2B1-deficent islets also had reduced insulin expression, insulin content, and glucose-stimulated insulin secretion. Heterozygous deletion of SH2B1 decreased pancreatic insulin content ...
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SH2B1 in β cells regulates glucose metabolism by promoting β cell survival and islet expansion
Diabetes, 2014Co-Authors: Zheng Chen, Lin Jiang, David Morris, Yong 刘勇 Liu, Liangyou RuiAbstract:IGF-1 and insulin promote β-cell expansion by inhibiting β-cell death and stimulating β-cell proliferation, and the phosphatidylinositol (PI) 3-kinase/Akt pathway mediates insulin and IGF-1 action. Impaired β-cell expansion is a risk factor for type 2 diabetes. Here, we identified SH2B1, which is highly expressed in β-cells, as a novel regulator of β-cell expansion. Silencing of SH2B1 in INS-1 832/13 β-cells attenuated insulin- and IGF-1–stimulated activation of the PI 3-kinase/Akt pathway and increased streptozotocin (STZ)-induced apoptosis; conversely, overexpression of SH2B1 had the opposite effects. Activation of the PI 3-kinase/Akt pathway in β-cells was impaired in pancreas-specific SH2B1 knockout (PKO) mice fed a high-fat diet (HFD). HFD-fed PKO mice also had increased β-cell apoptosis, decreased β-cell proliferation, decreased β-cell mass, decreased pancreatic insulin content, impaired insulin secretion, and exacerbated glucose intolerance. Furthermore, PKO mice were more susceptible to STZ-induced β-cell destruction, insulin deficiency, and hyperglycemia. These data indicate that SH2B1 in β-cells is an important prosurvival and proproliferative protein and promotes compensatory β-cell expansion in the insulin-resistant state and in response to β-cell stress.
