Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Xi, Yannan; Liu, Siming; Bettaieb, Ahmed; Matsuo, Kazuya; Matsuo, Izumi; Hosein, Ellen; Chahed, Samah; Wiede, Florian; Zhang, Sheng; Zhang, Zhong Yin; Kulkarni, Rohit; Tiganis, Tony; Haj, Fawaz G.

doi:10.1007/s00125-014-3413-7

Cited by 19 publications

(15 citation statements)

References 51 publications

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“…In STAT3 signaling, phosphosites in the mitogen-activated protein kinase 3 (Mapk3) and mitogen-activated protein kinase 1 (Mapk1) at Y205 and Y185 were upregulated, whereas dual specificity mitogen-activated protein kinase 2 (Map2k2) at S293 and proto-oncogene tyrosine-protein kinase (Src) were detected with significant downregulated phosphosites on proteins at 15 min of GSIS. Activated STAT3 phosphorylation and signaling enhanced GSIS in PBCs (37). The Rho family of small GTPase-mediated mTOR signaling is well known to be activated by glucose (38), and in the acute phase response signaling implicated in type 2 diabetes and the dysfunction of FIG.…”

Section: Gene Ontology Analysis Of Post-translationally Modified Protmentioning

confidence: 98%

Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic β-cells Using Post-translational Modification Specific Proteomics (PTMomics)

Kang

Jensen

Huang

et al. 2018

Molecular & Cellular Proteomics

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Normal pancreatic islet β-cells (PBCs) abundantly secrete insulin in response to elevated blood glucose levels, in order to maintain an adequate control of energy balance and glucose homeostasis. However, the molecular mechanisms underlying the insulin secretion are unclear. Improving our understanding of glucose-stimulated insulin secretion (GSIS) mechanisms under normal conditions is a prerequisite for developing better interventions against diabetes. Here, we aimed at identifying novel signaling pathways involved in the initial release of insulin from PBCs after glucose stimulation using quantitative strategies for the assessment of phosphorylated proteins and sialylated -linked (SA) glycoproteins.Islets of Langerhans derived from newborn rats with a subsequent 9-10 days of maturation were stimulated with 20 mm glucose for 0 min (control), 5 min, 10 min, and 15 min. The isolated islets were subjected to time-resolved quantitative phosphoproteomics and sialiomics using iTRAQ-labeling combined with enrichment of phosphorylated peptides and formerly SA glycopeptides and high-accuracy LC-MS/MS. Using bioinformatics we analyzed the functional signaling pathways during GSIS, including well-known insulin secretion pathways. Furthermore, we identified six novel activated signaling pathways ( agrin interactions and prolactin signaling) at 15 min GSIS, which may increase our understanding of the molecular mechanism underlying GSIS. Moreover, we validated some of the regulated phosphosites by parallel reaction monitoring, which resulted in the validation of eleven new phosphosites significantly regulated on GSIS. Besides protein phosphorylation, alteration in SA glycosylation was observed on several surface proteins on brief GSIS. Interestingly, proteins important for cell-cell interaction, cell movement, cell-ECM interaction and Focal Adhesion ( integrins, semaphorins, and plexins) were found regulated at the level of sialylation, but not in protein expression. Collectively, we believe that this comprehensive Proteomics and PTMomics survey of signaling pathways taking place during brief GSIS of primary PBCs is contributing to understanding the complex signaling underlying GSIS.

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Section: Gene Ontology Analysis Of Post-translationally Modified Protmentioning

confidence: 98%

Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic β-cells Using Post-translational Modification Specific Proteomics (PTMomics)

Kang

Jensen

Huang

et al. 2018

Molecular & Cellular Proteomics

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“…Recently, the role of PTPN2 in pancreatic endocrine function and insulin secretion was explored. In a study by Xi et al the deficiency in PTPN2 expression by knockout affected beta cell function in mice (Xi et al, 2015 ). The reduced insulin secretion wass associated with a decreased insulin content and glucose sensing, which showed that STAT3 could be a relevant target for the PTPN2 phosphatase regulation in the pancreas (Xi et al, 2015 ).…”

Section: Genetic Variations Of Ptpn2 and mentioning

confidence: 99%

“…In a study by Xi et al the deficiency in PTPN2 expression by knockout affected beta cell function in mice (Xi et al, 2015 ). The reduced insulin secretion wass associated with a decreased insulin content and glucose sensing, which showed that STAT3 could be a relevant target for the PTPN2 phosphatase regulation in the pancreas (Xi et al, 2015 ). PTPN2 regulates insulin signaling by inactivating its receptor through de-phosphorylation of the insulin receptor β-chain in conjunction with the PTP1B phosphatase.…”

Section: Genetic Variations Of Ptpn2 and mentioning

confidence: 99%

Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease

Sharp

Abdulrahim

Naser

et al. 2015

Front. Cell. Infect. Microbiol.

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Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non-receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease.

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“…All these findings show that decreased PTPN2 expression sensitizes beta-cells to apoptosis induced by danger signals, and SNPs within PTPN2 that evoke decreased expression or function may increase the risk of T1DM (8). In addition to apoptosis, insulin secretion is also potentially affected by PTPN2; a previous study found that PTPN2 knockout in mice affected beta-cell function and led to decreased insulin secretion (79).…”

Section: Ptpn2mentioning

confidence: 89%

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

et al. 2020

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T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.

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Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Cited by 19 publications

References 51 publications

Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic β-cells Using Post-translational Modification Specific Proteomics (PTMomics)

Characterization of the Molecular Mechanisms Underlying Glucose Stimulated Insulin Secretion from Isolated Pancreatic β-cells Using Post-translational Modification Specific Proteomics (PTMomics)

Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM

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