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Ammonia nitrogen is a common environmental factor in aquaculture systems. High levels of ammonia nitrogen threaten the health of shrimp. This study aimed to investigate ammonia nitrogen stress in the hepatopancreas of Penaeus vannamei by integrating physiological, metabolome, and transcriptome analysis. The study revealed that exposure to ammonia nitrogen resulted in injury to the hepatopancreas, deformation disorder of the lumen, blurred boundaries, and increased vacuoles. After ammonia nitrogen stress, the activities of ammonia-metabolizing enzymes (glutamate dehydrogenase and glutamine synthetase) increased significantly, while the activity of transglutaminase decreased significantly. In addition, antioxidant enzymes (glutathione peroxidase, catalase, and superoxide dismutase) were significantly decreased. Additionally, the activity of energy metabolizing enzyme (hexokinase) was increased, and immune enzyme (alkaline phosphatase) activity was decreased. The accumulation of metabolites, such as d-myo-inositol, hexadecenoic acid, aspartate, and ornithine in the metabolite groups, showed significant differences under ammonia stress. Transcriptome analysis suggested that the KEGG pathways were significantly enriched in energy and primary metabolism, metabolism of cofactors and vitamins, and signaling pathways. The comprehensive analysis of metabolome and transcriptome displayed significant enrichment pathways, including TCA cycle, purine metabolism, pyrimidine metabolism, and folic acid biosynthesis under ammonia nitrogen stress. Simultaneously, six genes were found to respond to ammonia stress, including inositol oxygenase-like, histone h1-β, postembryonic, blood cell protein-glutamine-glutamyltransferase-like, receptor tyrosine protein phosphatase T-like, trichohyalin-like, and thyroxine 5-deiodinase-like. The results showed that ammonia nitrogen stress caused hepatopancreas tissue damage, changed in enzyme activities, metabolic process, and related gene expression in P. vannamei. [ABSTRACT FROM AUTHOR]

Reversible protein phosphorylation, known as the "switch" of the cell, is controlled by protein kinases (PKs) and protein phosphatases (PPs). Based on substrate specificity, PPs are classified into protein serine/threonine phosphatases and protein tyrosine phosphatases (PTPs). PTPs can dephosphorylate phosphotyrosine and phosphoserine/phosphothreonine. In plants, PTPs monitor plant physiology, growth, and development. This review summarizes an overview of the PTPs' classification and describes how PTPs regulate various plant processes, including plant growth and development, plant hormone responses, and responses to abiotic and biotic stresses. Then, future research directions on the PTP family in plants are discussed. This summary will serve as a reference for researchers studying PTPs in plants. [ABSTRACT FROM AUTHOR]

The prevalence of small multi-target drugs containing a fluorinated aromatic moiety among approved drugs in the market is due to the unique properties of this halogen atom. With the aim to develop potent antidiabetic agents, a series of phenylsulfonic esters based on the conjugation of the 5-substituted 2-hydroxy-3-nitroacetophenones 1a–d with phenylsulfonyl chloride derivatives substituted with a fluorine atom or fluorine-containing (-CF3 or -OCF3) group were prepared. Their structures were characterized using a combination of spectroscopic techniques complemented with a single-crystal X-ray diffraction (XRD) analysis on a representative example. The compounds were, in turn, assayed for inhibitory effect against α-glucosidase, α-amylase, protein tyrosine phosphatase 1 B (PTP1B) and the vascular endothelial growth factor receptor-2 (VEGFR-2) all of which are associated with the pathogenesis and progression of type 2 diabetes mellitus (T2DM). The antigrowth effect of selected compounds was evaluated on the human breast (MCF-7) and lung (A549) cancer cell lines. The compounds were also evaluated for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness. [ABSTRACT FROM AUTHOR]

Protein-protein interactions (PPIs) play pivotal roles in directing T cell fate. One key player is the non-receptor tyrosine protein kinase Lck that helps to transduce T cell activation signals. Lck is mediated by other proteins via interactions that are inadequately understood. Here, we use the deep learning method AF2Complex to predict PPIs involving Lck, by screening it against ∼1,000 proteins implicated in immune responses, followed by extensive structural modeling for selected interactions. Remarkably, we describe how Lck may be specifically targeted by a palmitoyltransferase using a phosphotyrosine motif. We uncover "hotspot" interactions between Lck and the tyrosine phosphatase CD45, leading to a significant conformational shift of Lck for activation. Lastly, we present intriguing interactions between the phosphotyrosine-binding domain of Lck and the cytoplasmic tail of the immune checkpoint LAG3 and propose a molecular mechanism for its inhibitory role. Together, this multifaceted study provides valuable insights into T cell regulation and signaling. [Display omitted] • Lck SH2 and SH3 domains are predicted to have multiple interaction partners • Palmitoyltransferase zDHHC18 targets Lck via a phosphotyrosine motif • CD45 interacts with Lck at hotspots to activate Lck • LAG3's cytoplasmic tail blocks access to the SH2 domain of Lck Gao and Skolnick use deep learning to identify protein-protein interaction partners of tyrosine kinase Lck among ∼1,000 immune-related proteins. Predicted structures for several complexes reveal potential molecular mechanisms, providing insights into their functions in T cell regulation and signaling. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene have been documented to be linked with several autoimmune disorders including Behçet's disease (BD). PTPN2 SNPs rs2542151 and rs7234029 have been assessed using real-time PCR in 96 BD patients and 50 controls matched by age and gender. Patients were categorized into groups according to the disease phenotypes and severity. A total of 94.8% of patients were males. The patients' mean age at onset was 26.1 ± 8 years. The median (IQR) disease duration was 8.5(4–13) years. No difference was observed between the patients and controls concerning the frequency of the two SNPs' different genotypes, models, and alleles. Moreover, neither disease phenotypes nor severity were associated with rs2542151 or rs7234029 SNPs. PTPN2 rs2542151 and rs7234029 SNPs do not seem to have associations with BD occurrence, phenotypes, or severity in the Egyptian patients. Key Points • PTPN2 rs2542151 and rs7234029 SNPs do not seem to have associations with BD occurrence, phenotypes, or severity in the Egyptian patients. • Further studies involving a larger sample size with variable clinical diversity are recommended to verify the results. [ABSTRACT FROM AUTHOR]

High stemness index scores are associated with poor survival in patients with lung cancer. Studies on the mRNA expression-based stemness index (mRNAsi) are typically conducted using tumor tissues; however, mRNAsi-related expression signatures based on cell-free RNA (cfRNA) are yet to be comprehensively investigated. The present study aimed to elucidate the gene expression profiles of tumor stemness in lung cancer tissues and corresponding cfRNAs in blood, and to assess their links with immune infiltration. Tumor tissue, paracancerous tissue, peripheral blood and lymph node samples were collected from patients with stage I-III non-small cell lung cancer and RNA sequencing was performed. The TCGAbiolinks package was used to calculate the mRNAsi for each of these four types of sample. Weighted gene co-expression network analysis and differentially expressed gene analyses were performed to investigate mRNAsi-related genes, and pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology-based annotation system. In addition, the STAR-Fusion tool was used to detect fusion variants, and CIBERSORT was used to analyze the correlations of stemness signatures in tissues and blood with immune cell infiltration. The mRNAsi values in peripheral blood and lymph nodes were found to be higher than those in cancer tissues. 'Hematopoietic cell lineage' was the only KEGG pathway enriched in mRNAsi-related genes in both lung cancer tissues and peripheral blood. In addition, the protein tyrosine phosphatase receptor type C associated protein gene was the only gene commonly associated with the mRNAsi in these two types of sample. The expression of mRNAsi-related genes was increased in the dendritic and Treg cells in tumor tissues, but was elevated in Treg and CD8 cells in the blood. In conclusion, cfRNAs in the blood exhibit unique stemness signatures that have potential for use in the diagnosis of lung cancer. [ABSTRACT FROM AUTHOR]

Epidemiological surveys have shown that the incidence of type 2 diabetes mellitus (T2DM) and malignancies is rapidly increasing worldwide and has become a major disease that threatens human life. In this study, we quantitatively analyzed the proteome of tumor tissues and adjacent normal tissues from six patients withT2DM combined with colorectal cancer (CRC) and eight non-diabetic CRC, focusing on the effect of T2DM on tumor tissues. We analyzed the functional enrichment of differentially expressed proteins (DEPs) using clusterProfiler in R and the expression level of protein tyrosine phosphatase non-receptor type 11 (PTPN11) and other key proteins in the TIMER and GEPIA2 databases. The HPA database was used to validate PTPN11 protein expression. The correlation between PTPN11 expression and clinicopathological features was analyzed by UALCAN database. The impact of PTPN11 on clinical prognosis was evaluated utilizing Kaplan-Meier Plotter. The correlation between PTPN11 expression and tumor-infiltrated immune cells was investigated via TIMER and TISIDB databases. Gene set enrichment analysis (GSEA) was performed to examined the pathway of PTPN11 enrichment in CRC using data from The Cancer Genome Atlas (TCGA) database. Furthermore, small interfering (si) RNA was used to knock down PTPN11 in CRC cell line SW480. Western blot analysis was used to detect PTPN11 expression in tissue samples or cells and the effect of PTPN11 knockdown on key proteins related to PI3K/AKT and cell cycle pathway in SW480 cells. Cell proliferation and wound healing assays were used to detect the effects of cell proliferation and migration after knockdown of PTPN11 or treatment with high glucose. We found that metabolic pathways such as oxidative phosphorylation, glycolysis/gluconeogenesis, and insulin secretion were significantly enriched in tumor tissues from diabetic patients compared to non-diabetic patients. In addition, PTPN11, a marker gene associated with T2DM and CRC, were mined in diabetic tumor tissues. PTPN11 showed high expression in diabetic tumor tissues compared to normal tissues. High PTPN11 expression predicted poor prognosis in CRC. PTPN11 expression was strongly associated with immune infiltrating cells in CRC. GSEA analysis revealed that PTPN11 was enriched in cancer-related pathways. Western blotting analysis indicated that PTPN11 knockdown reduced the protein levels of p-PI3K, p-AKT, CDK1 and CYCLIN D, without altering PI3K and AKT protein levels. Cell proliferation and wound healing data showed that PTPN11 and high glucose could increase the proliferation and migration ability. These findings showed that PTPN11 may be a potential key biomarker for CRC in patients with diabetes, which will provide new potential targets for future intervention of T2DM complicated with CRC. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with the proliferation and activation of myofibroblasts being definite effectors and drivers. Here, increased expression of Meis1 (myeloid ecotropic viral integration site 1) is observed, predominantly in the nucleus of the kidney of CKD patients and mice, and negatively correlates with serum creatinine. Fibroblast‐specific knock‐in of Meis1 inhibits myofibroblast activation and attenuates renal fibrosis and kidney dysfunction in CKD models. Overexpression of Meis1 in NRK‐49F cells suppresses the pro‐fibrotic response induced by transforming growth factor‐β1 but accelerates by its knockdown. Mechanistically, Meis1 targets protein tyrosine phosphatase receptor J (Ptprj) to block renal fibrosis by inhibiting the proliferation and activation of fibroblasts. Finally, a new activator of Ptprj is identified through computer‐aided virtual screening, which has the effect of alleviating renal fibrosis. Collectively, these results illustrate that the Meis1/Ptprj axis has therapeutic potential for clinically treating CKD. [ABSTRACT FROM AUTHOR]

Hypertension is associated with poor outcome and higher mortality in patients with ischemic stroke. The impairment of adaptive vascular mechanisms under hypertensive condition compromises collateral blood flow after arterial occlusion in patients with acute ischemic stroke resulting in hypoperfusion. The increased oxidative stress caused by hypoperfusion is thought to be a trigger for the rapid evolution of ischemic infarct volume under hypertensive condition. However, the cellular factors and pathways that contribute to the exacerbation of ischemic brain injury under hypertensive condition is not yet understood. The current study reveals that predisposition to hypertension leads to basal loss of function of the neuron-specific tyrosine phosphatase STEP, which plays a crucial role in neuroprotection against excitotoxic insult. The findings further show that a mild ischemic insult in hypertensive rats triggers an early onset and sustained activation of the neuronal extracellular signal regulated kinase (ERK MAPK), a member of the mitogen activated protein kinase family and a substrate of STEP. This leads to rapid increase in the activation of neuronal NF-κB, expression of neuronal cyclooxygenase-2 and subsequent biosynthesis of the pro-inflammatory mediator prostaglandin E2, resulting in rapid morphological transformation of microglia to the pro-inflammatory state and subsequent exacerbation of ischemic brain injury. Restoration of STEP signaling with intravenous administration of a STEP-derived peptide mimetic reduces the pro-inflammatory response in neurons, activation of microglia, and ischemic brain injury. The findings suggest that the basal loss of STEP function under hypertensive condition contributes to the exacerbation of ischemic brain injury by enhancing post-ischemic inflammatory response. The study not only presents a novel role of STEP in regulating neuroimmune communication but also highlights the therapeutic potential of a STEP-mimetic in mitigating ischemic brain damage under hypertensive condition. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications MicroRNA (miR)‐210 function in endothelial cells and its role in diabetes‐associated endothelial dysfunction are not fully understood. We aimed to characterize the miR‐210 function in endothelial cells and study its therapeutic potential in diabetes.Two different diabetic mouse models (db/db and Western diet‐induced), miR‐210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.miR‐210 levels were lower in aortas isolated from db/db than in control mice. Endothelium‐dependent relaxation (EDR) was impaired in aortas from miR‐210 knockout mice, and this was restored by inhibiting miR‐210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol‐3‐phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR‐210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR‐210. However, plasma miR‐210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR‐210 transgenic mice and pharmacological overexpression using miR‐210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR‐210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR‐210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.This study unravels the mechanisms by which down‐regulated miR‐210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR‐210 serves as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Toxocara canis, the most prevalent helminth in dogs and other canines, is one of the socioeconomically important zoonotic parasites, particularly affecting pediatric and adolescent populations in impoverished communities. However, limited information is available regarding the proteomes of female and male adult T. canis. To address this knowledge gap, we performed a comprehensive proteomic analysis to identify the proteins with differential abundance (PDAs) and gender-specifically expressed proteins between the two sexes adult T. canis. Methods: The comparative proteomic analysis was carried out by the Orbitrap mass spectrometry (MS) with asymmetric track lossless (Astral) analyzer. The difference analysis was conducted using t-test and the proteins verification was achieved through parallel reaction monitoring (PRM). The potential biological functions of identified adult T. canis proteins and PDAs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The domain, transcription factor and subcellular localization of the identified proteins and PDAs were analyzed by InterPro, AnimalTFDB 4.0 and Cell-mPLOC 2.0 databases, respectively. Results: A total of 8565 somatic proteins of adult T. canis were identified. Compared to male adult, 682 up-regulated PDAs and 844 down-regulated PDAs were identified in female adult with P-values < 0.05 and |log2FC| > 1, including 139 proteins exclusively expressed in female and 272 proteins exclusively expressed in male. The GO annotation analysis using all PDAs revealed that the main biological processes, cellular components and molecular functions corresponded to aminoglycan metabolic process, extracellular region and protein tyrosine phosphatase activity, respectively. The KEGG analysis using all PDAs showed that the pathways were mainly associated with adipocytokine signaling pathway, proximal tubule bicarbonate reclamation and PPAR signaling pathway. Conclusions: This study reveals the differential protein expression between female and male adult T. canis, providing valuable resource for developing the novel intervention strategies against T. canis infection in humans and animals, especially from the perspective of sexual development and reproduction. [ABSTRACT FROM AUTHOR]

The adaptor protein tumor necrosis factor receptor-associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T-cell activation and function. TRAF3 regulates signals mediated by the T-cell receptor (TCR), costimulatory molecules, and cytokine receptors, which each drive activation of the serine/threonine kinase Akt. The impact of TRAF3 upon TCR-CD28-mediated activation of Akt, and thus on the diverse cellular processes regulated by Akt, including CD4 T-cell fate decisions, remains poorly understood. We show here that TRAF3 deficiency led to impaired Akt activation and thus to impaired in vitro skewing of CD4 T cells into the TH1 and TH2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive TH1 and TH2 differentiation and found that TRAF3 enhanced activation of signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the TH2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule protein tyrosine phosphatase 1B to the IL-4R signaling complex, in a manner that required integration of TCR-CD28- and IL-4R-mediated signals. This work reveals a new mechanism for TRAF3-mediated regulation of STAT6 activation in CD4 T cells and adds to our understanding of the diverse roles played by TRAF3 as an important regulator of T-cell biology. [ABSTRACT FROM AUTHOR]

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC90 values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC90 value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC50 values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. [ABSTRACT FROM AUTHOR]

Pleiotrophin (PTN) is a secreted factor that regulates endothelial cell migration through protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) and αvβ3 integrin. Genetic deletion of Ptprz1 results in enhanced endothelial cell proliferation and migration, due to the decreased expression of β3 integrin and the subsequent, enhanced cMet phosphorylation. In the present study, we investigated the effect of PTN and PTPRZ1 on activating the mTORC1 kinase and protein synthesis and identified part of the implicated signaling pathway in endothelial cells. PTN or genetic deletion of Ptprz1 activates protein synthesis in a mTORC1-dependent manner, as shown by the enhanced phosphorylation of the mTORC1-downstream targets ribosomal protein S6 kinase 1 (SK61) and 4E-binding protein 1 (4EBP1) and the upregulation of HIF-1α. The cMet tyrosine kinase inhibitor crizotinib abolishes the stimulatory effects of PTN or PTPRZ1 deletion on mTORC1 activation and protein synthesis, suggesting that mTORC1 activation is downstream of cMet. The mTORC1 inhibitor rapamycin abolishes the stimulatory effect of PTN or PTPRZ1 deletion on endothelial cell migration, suggesting that mTORC1 is involved in the PTN/PTPRZ1-dependent cell migration. The αvβ3 integrin blocking antibody LM609 and the peptide PTN112–136, both known to bind to ανβ3 and inhibit PTN-induced endothelial cell migration, increase cMet phosphorylation and activate mTORC1, suggesting that cMet and mTORC1 activation are required but are not sufficient to stimulate cell migration. Overall, our data highlight novel aspects of the signaling pathway downstream of the PTN/PTPRZ1 axis that regulates endothelial cell functions. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) poses significant health risks to both mothers and infants, emphasizing the need for early detection strategies to mitigate its impact. However, the existing diagnostic methods, particularly the oral glucose tolerance test (OGTT) administered in the second or third trimester, show limitations in the detection of GDM during its early stages. This study aimed to explore the potential of the genes Protein Tyrosine Phosphatase Receptor-type Gamma (PTPRG) and Immunoglobulin Kappa Variable 2D-28 (IGKV2D-28) as early indicators for GDM among Filipino pregnant women. Utilizing reverse transcription–quantitative polymerase chain reaction (RT-qPCR), the gene expressions were analyzed in first-trimester blood samples obtained from 24 GDM and 36 non-GDM patients. The diagnostic performance of PTPRG and IGKV2D-28 was analyzed and evaluated using receiver operating characteristic (ROC) curves. The findings revealed elevated expression levels of PTPRG and IGKV2D-28 within the GDM cohort. Remarkably, PTPRG exhibited a sensitivity of 83%, while IGKV2D-28 demonstrated a specificity of 94% at determined cut-off values. Combining both genes yielded an improved but limited diagnostic accuracy with an area under the curve (AUC) of 0.63. This preliminary investigation of PTPRG and IGKV2D-28 sheds light on novel avenues for early GDM detection. While these findings are promising, further validation studies in larger cohorts are necessary to confirm these results and explore additional biomarkers to enhance diagnostic precision in GDM pregnancies and, ultimately, to improve maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases (PTPs) play central roles in the regulation of cell signaling, organismal development, cellular differentiation and proliferation, and cancer. In the immune system, PTPs regulate the activation, differentiation and effector function of lymphocytes and myeloid cells whilst single-nucleotide polymorphisms (SNPs) in PTP-encoding genes have been identified as risk factors for the development of autoimmunity. In this review we describe the roles for PTP nonreceptor type 22 (PTPN22) in the regulation of T lymphocyte signaling and activation in autoimmunity, infection and cancer. We summarize recent progress in our understanding of the regulation of PTPN22 activity, the impact of autoimmune disease-associated PTPN22 SNPs on T cell responses and describe approaches to harness PTPN22 as a target to improve T cell-based immunotherapies in cancer. [ABSTRACT FROM AUTHOR]

Prenatal stress may lead to tissue- and sex-specific cardiometabolic disorders in the offspring through imbalances in the insulin signaling pathway. Therefore, we aimed to determine the sex-specific adaptations of prenatal stress on the insulin signaling pathway of cardiac and hepatic tissue of adult offspring Wistar rats. Wistar pregnant rats were divided into control and stress groups. Unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. After lactation, the dams were euthanized, and blood was collected for corticosterone measurement and the offspring were separated into four groups according to sex and intervention (n = 8/group). At 90 days old, the offspring were submitted to an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). After euthanasia, blood collection was used for biochemical analysis and the left ventricle and liver were used for protein expression and histological analysis. Stress increased maternal corticosterone levels. It also increased glucose concentration in both OGTT and ITT and reduced insulin receptor (Irβ) and insulin receptor substrate-1 (IRS1) activation, while reducing the insulin receptor inhibition [protein tyrosine phosphatase 1B (PTP1B)] in the liver of male offspring at 90 days old, without repercussions in cardiac tissue. Moreover, female offspring submitted to prenatal stress exhibited reduced fatty acid uptake, with lower hepatic CD36 expression, reduced high-density lipoprotein cholesterol (cHDL), and increased Castelli risk indexes I and II. Unpredictable prenatal stress evoked reduced insulin sensitivity and liver-specific impairment in insulin signaling activation in male while increasing markers of cardiovascular risk in females. NEW & NOTEWORTHY: Prenatal stress may contribute to tissue-specific programming, especially in the liver. Our results showed that, although there were no repercussions to stress in cardiac tissue at 90 days old, prenatal stress induces a glucose intolerance phenotype with insulin signaling pathway alterations in the liver of male offspring at 90 days old. Furthermore, the prenatal stress altered lipid profile and increased cardiovascular risk in female offspring. [ABSTRACT FROM AUTHOR]

Background: Protein tyrosine phosphatase non‐receptor type 7 (PTPN7) is a signaling molecule that regulates a multitude of cellular processes, spanning cell proliferation, cellular differentiation, the mitotic cycle, and oncogenic metamorphosis. However, the characteristic of PTPN7 in the glioma microenvironment has yet to be elucidated. Methods: The prognostic value, genomic features, immune characteristics, chemotherapy prediction, and immunotherapy prediction of PTPN7 were systematically explored at the bulk sequencing level. The cell evolution trajectory, cell communication pattern, and cell metabolic activity related to PTPN7 were systematically explored at the single‐cell sequencing level. HMC3 and M0 cells were cocultured with U251 and T98G cells, and flow cytometry was carried out to investigate the polarization of HMC3 and M0. Transwell assay and CCK‐8 assay were performed to explore the migration and proliferation activity of U251 and T98G. Results: The expression level of PTPN7 is significantly elevated in glioma and indicates malignant features. PTPN7 expression predicts worse prognosis of glioma patients. PTPN7 is associated with genome alteration and immune infiltration. Besides, PTPN7 plays a crucial role in modulating metabolic and immunogenic processes, particularly by influencing the activity of microglia and macrophages through multiple signaling pathways involved in cellular communication. Specifically, PTPN7 actively mediates inflammation‐resolving‐polarization of macrophages and microglia and protects glioma from immune attack. PTPN7 could also predict the response of immunotherapy. Conclusions: PTPN7 is critically involved in inflammation‐resolving‐polarization mediated by macrophage and microglia and promotes the immune escape of glioma cells. [ABSTRACT FROM AUTHOR]

The expression "Autoimmune/inflammatory syndrome induced by adjuvants (ASIA)" was coined by Shoenfeld and colleagues in 2011. It defines a group of immune-mediated disorders that arise in people, with a genetic predisposition, following exposure to adjuvant agents. This syndrome has been reported after contact with silicone implants, medications, infections, metals, vaccines, and other substances. It typically occurs in individuals with a genetic predisposition, particularly involving genes, such as HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) and PTPN22 (protein tyrosine phosphatase non-receptor type 22). Some stimuli lead to an overactivation of the immune system, prompt the production of autoantibodies, and finally cause autoimmune disorders. This narrative review aims to provide an overview of the ASIA syndrome with a special focus on the role of adjuvants in different vaccines, especially after the COVID-19 pandemic, and insights into development of new treatments. [ABSTRACT FROM AUTHOR]

Fucosylated chondroitin sulfate (FCS) was prepared from Bohadschia ocellata using protease hydrolysis. The structural characteristics of FCS were confirmed through chemical composition analysis using FTIR spectroscopy, 1H NMR, and 13C NMR. FCS from B. ocellata (FCS-Bo) exhibited an average molecular weight of approximately 122 kDa. The biological activities of FCS-Bo, including anticoagulant, anti-cancer, and Protein Tyrosine Phosphatase 1B (PTP1B) inhibition, were evaluated. FCS-Bo displayed potent anticoagulant properties, markedly extending activated partial thromboplastin time, prothrombin time, and thrombin time when compared to the heparin control. In anti-cancer bioactivity research, FCS-Bo efficiently inhibited colony formation in the colon cancer cell lines HCT-116, HT-29, and DLD-1, achieving inhibition rates of up to 65%. Additionally, FCS-Bo exhibited significant inhibition of PTP1B, with an IC50 as low as 0.0326 µg/mL, suggesting its potential for improving insulin sensitivity and managing conditions such as type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]

Simulation datasets of proteins (e.g., those generated by molecular dynamics simulations) are filled with information about how a non-covalent interaction network within a protein regulates the conformation and, thus, function of the said protein. Most proteins contain thousands of non-covalent interactions, with most of these being largely irrelevant to any single conformational change. The ability to automatically process any protein simulation dataset to identify non-covalent interactions that are strongly associated with a single, defined conformational change would be a highly valuable tool for the community. Furthermore, the insights generated from this tool could be applied to basic research, in order to improve understanding of a mechanism of action, or for protein engineering, to identify candidate mutations to improve/alter the functionality of any given protein. The open-source Python package Key Interactions Finder (KIF) enables users to identify those non-covalent interactions that are strongly associated with any conformational change of interest for any protein simulated. KIF gives the user full control to define the conformational change of interest as either a continuous variable or categorical variable, and methods from statistics or machine learning can be applied to identify and rank the interactions and residues distributed throughout the protein, which are relevant to the conformational change. Finally, KIF has been applied to three diverse model systems (protein tyrosine phosphatase 1B, the PDZ3 domain, and the KE07 series of Kemp eliminases) in order to illustrate its power to identify key features that regulate functionally important conformational dynamics. [ABSTRACT FROM AUTHOR]

Kaempferol is a flavonol identified as the most potent activator of chloride (Cl-) secretion among other flavonoids in airway epithelial cells. This study aimed to investigate the cellular mechanisms by which kaempferol stimulates Cl- secretion in the T84 human colon carcinoma cell line by Ussing chambers and voltage clamp technique. Bilateral addition of kaempferol (1-100 µM) increased shortcircuit current (Isc) in a concentration-dependent manner. Ion substitution of Cl- or CFTR inhibitors NPPB and glibenclamide or a Na+/K+/2Cl- cotransporter inhibitor bumetanide attenuated kaempferol-induced Isc response. In permeabilized monolayers, selective channel inhibitors CFTRinh-172 and CaCCinh-A01 inhibited kaempferol-induced apical Cl- current (ICl), and K+ blockers BaCl2 and clotrimazole inhibited basolateral K+ current (IKb). The kaempferol-induced ICl showed no additive effects with forskolin or 8cptcAMP. The kaempferol-induced ICl was mostly abolished by protein kinase A inhibitor H89, but not by tyrosine kinase inhibitors, AG490 and tyrphostin A23, or tyrosine phosphatase inhibitor vanadate. Treatment with kaempferol for 24 h increased the expression of CFTR protein as determined by the Western blot analysis. These results demonstrated that kaempferol activates Cl- secretion across T84 cells by activating the apical Cl- current and basolateral K+ current. The mechanisms may involve the cAMP/PKA pathway and CFTR expression. Taken together, these findings reveal the beneficial effects of kaempferol to increase fluid secretion which can be used to treat constipation. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end‐stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity. Tie2 signaling is negatively regulated by the endothelial specific transmembrane receptor Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion of VEPTP protects from hypertension and diabetes induced renal injury in a mouse model of DKD. Here, we show that VEPTP inhibition with an extracellular domain targeting VEPTP antibody induced Tie2 phosphorylation and improved VEGF‐A induced vascular permeability both in vitro and in vivo. Treatment with the VEPTP blocking antibody decreased the renal expression of endothelial activation markers (Angpt2, Edn1, and Icam1) but failed to improve kidney function in db/db uninephrectomized ReninAAV DKD mice. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) was found to be a critical element in the pathogenesis of Parkinson's disease (PD), facilitating abnormal α-synuclein (α-Syn) aggregation in neurons and thus promoting PD development. However, how IR contributes to abnormal α-Syn aggregation remains ill-defined. Here, we analyzed six PD postmortem brain transcriptome datasets to reveal module genes implicated in IR-mediated α-Syn aggregation. In addition, we induced IR in cultured dopaminergic (DA) neurons overexpressing α-Syn to identify IR-modulated differentially expressed genes (DEGs). Integrated analysis of data from PD patients and cultured neurons revealed 226 genes involved in α-Syn aggregation under IR conditions, of which 53 exhibited differential expression between PD patients and controls. Subsequently, we conducted an integrated analysis of the 53 IR-modulated genes employing transcriptome data from PD patients with different Braak stages and DA neuron subclasses with varying α-Syn aggregation scores. Protein tyrosine phosphatase receptor type O (PTPRO) was identified to be closely associated with PD progression and α-Syn aggregation. Experimental validation in a cultured PD cell model confirmed that both mRNA and protein of PTPRO were reduced under IR conditions, and the downregulation of PTPRO significantly facilitated α-Syn aggregation and cell death. Collectively, our findings identified PTPRO as a key regulator in IR-mediated α-Syn aggregation and uncovered its prospective utility as a therapeutic target in PD patients with IR. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, characterized by excess lipid deposition. Insulin resistance (IR) serves as a fundamental pathogenic factor in MAFLD. However, currently, there are no approved specific agents for its treatment. Farrerol, a novel compound with antioxidant and anti‐inflammatory effects, has garnered significant attention in recent years due to its hepatoprotective properties. Despite this, the precise underlying mechanisms of action remain unclear. In this study, a network pharmacology approach predicted protein tyrosine phosphatase non‐receptor type 1 (PTPN1) as a potential target for farrerol's action in the liver. Subsequently, the administration of farrerol improved insulin sensitivity and glucose tolerance in MAFLD mice. Furthermore, farrerol alleviated lipid accumulation by binding to PTPN1 and reducing the dephosphorylation of the insulin receptor (INSR) in HepG2 cells and MAFLD mice. Thus, the phosphoinositide 3‐kinase/serine/threonine‐protein kinases (PI3K/AKT) signalling pathway was active, leading to downstream protein reduction. Overall, the study demonstrates that farrerol alleviates insulin resistance and hepatic steatosis of MAFLD by targeting PTPN1. [ABSTRACT FROM AUTHOR]

Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a Ptprj knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR‐Cas9 gene editing. Ptprj KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS‐1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca2+ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth. [ABSTRACT FROM AUTHOR]

Aims SCUBE2 (signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) is a secreted or membrane-bound protein originally identified from endothelial cells (ECs). Our previous work showed that SCUBE2 forms a complex with E-cadherin and stabilizes epithelial adherens junctions (AJs) to promote epithelial phenotypes. However, it remains unclear whether SCUBE2 also interacts with vascular endothelial (VE)-cadherin and modulates EC barrier function. In this study, we investigated whether and how SCUBE2 in ECs regulates vascular barrier maintenance. Methods and results We showed that SCUBE2 colocalized and interacted with VE-cadherin and VE-protein tyrosine phosphatase (VE-PTP) within EC AJs. Furthermore, SCUBE2 knockdown disrupted EC AJs and increased EC permeability. Expression of EC SCUBE2 was suppressed at both mRNA and protein levels via the nuclear factor-κB signalling pathway in response to pro-inflammatory cytokines or permeability-inducing agents. In line with these findings, EC-specific deletion of Scube2 (EC-KO) in mice impaired baseline barrier function and worsened vascular leakiness of peripheral capillaries after local injection of histamine or vascular endothelial growth factor. EC-KO mice were also sensitive to pulmonary vascular hyperpermeability and leucocyte infiltration in response to acute endotoxin- or influenza virus-induced systemic inflammation. Meanwhile, EC-specific SCUBE2-overexpressing mice were protected from these effects. Molecular studies suggested that SCUBE2 acts as a scaffold molecule enabling VE-PTP to dephosphorylate VE-cadherin, which prevents VE-cadherin internalization and stabilizes EC AJs. As such, loss of SCUBE2 resulted in hyperphosphorylation of VE-cadherin at tyrosine 685, which led to its endocytosis, thus destabilizing EC AJs and reducing barrier function. All of these effects were exacerbated by inflammatory insults. Conclusion We found that SCUBE2 contributes to vascular integrity by recruiting VE-PTP to dephosphorylate VE-cadherin and stabilize AJs, thereby promoting EC barrier function. Moreover, our data suggest that genetic overexpression or pharmacological up-regulation of SCUBE2 may help to prevent vascular leakage and oedema in inflammatory diseases. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA‐approved medication for type II diabetes mellitus, has recently gained attention for its promising anti‐aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI‐1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI‐1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3‐kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very‐low‐density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age‐related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life. [ABSTRACT FROM AUTHOR]

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the CD33 locus. It has been determined that the risk variant associated with AD increases the expression of the large isoform of CD33 (CD33M) in innate immune cells and alters its biological functions. CD33 is thought to signal via the interaction of its ITIM motif and the protein tyrosine phosphatase, SHP-1. Here, we utilize different molecular and computational approaches to investigate how AD-associated genetic variation in CD33 affects its interaction with SHP-1 in human microglia and microglia-like cells. Our findings demonstrate a genotype-dependent interaction between CD33 and SHP-1, which may functionally contribute to the AD risk associated with this CD33 variant. We also found that CD33-PTPN6 (SHP-1) gene–gene interactions impact AD-related traits, while CD33-PTPN11 (SHP-2) interactions do not. [ABSTRACT FROM AUTHOR]

Chondroitin sulfate (CS) is a linear polysaccharide chain of alternating residues of glucuronic acid (GlcA) and N -acetylgalactosamine (GalNAc), modified with sulfate groups. Based on the structure, CS chains bind to bioactive molecules specifically and regulate their functions. For example, CS whose GalNAc is sulfated at the C4 position, termed CSA, and CS whose GalNAc is sulfated at both C4 and C6 positions, termed CSE, bind to a malaria protein VAR2CSA and receptor type of protein tyrosine phosphatase sigma (RPTPσ), respectively, in a specific manner. Here, we modified CSA and CSE chains with phosphatidylethanolamine (PE) at a reducing end, attached them to liposomes containing phospholipids and generated CSA and CSE liposomes. The CS-PE was incorporated into the liposome particles efficiently. Inhibition ELISA revealed specific interaction of CSA and CSE with recombinant VAR2CSA and RPTPσ, respectively, more efficiently than CS chains alone. Furthermore, CSE liposome was specifically incorporated into RPTPσ-expressing HEK293T cells. These results indicate CS liposome as a novel and efficient drug delivery system, especially for CS-binding molecules. [ABSTRACT FROM AUTHOR]

The protein tyrosine phosphatase 1B (PTP1B) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). Many PTP1B inhibitors have been reported, however, most of them lack high specificity and have adverse effects. Designing effective PTP1B inhibitors requires understanding the molecular mechanism of action between inhibitors and PTP1B. To this end, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann Surface Area (MM-PB/ SA) methods were used to observe the binding patterns of compounds with similar pentacyclic triterpene parent ring structures but different inhibition abilities. Through structure and energy analysis, we found that the positions of cavities and substituents significantly affect combining capacity. Besides, we constructed a series of potential inhibitor molecules using LUDI and rational drug design methods. The ADMET module of Discovery Studio 2020 was used to predict the properties of these inhibitor molecules. Lastly, we obtained compounds with low toxicity and significant inhibitory activity. The study will contribute to the treatment of T2DM. [ABSTRACT FROM AUTHOR]

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making. Editor's summary: Non–small cell lung cancer can be treated with anti–programmed death 1/ligand 1 (anti–PD-1/L1); however, biomarkers for response are imprecise. Here, Chen et al. evaluate the loss of protein tyrosine phosphatase receptor type T (PTPRT) as a predictor of response to anti–PD-1/L1 therapy. They show in mouse models that PTPRT-deficient tumors rely on the STING pathway to respond to anti–PD-1 therapy, and this study can help stratify patients who would benefit from this therapy. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators to overcome this resistance is vital for improving patient outcomes. In this study, a genome‐wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine‐protein phosphatase nonreceptor type 14 (PTPN14) as a key regulator of anoikis resistance. PTPN14 expression has shown a progressive decrease from normal breast tissue to metastatic tumors. Overexpressing PTPN14 has induced anoikis and inhibited cell proliferation in TNBC cells, while normal human breast cells are unaffected. Mechanistically, PTPN14 is identified as a key factor in dephosphorylating breast cancer antiestrogen resistance 3, a novel substrate, leading to the subsequent inhibition of PI3K/AKT and ERK signaling pathways. Local delivery of in vitro transcribed PTPN14 mRNA encapsulated by lipid nanoparticles in a TNBC mouse model has effectively inhibited tumor growth and metastasis, prolonging survival. The study underscores PTPN14 as a potential therapeutic target for metastatic TNBC, with the therapeutic strategy based on mRNA expression of PTPN14 demonstrating clinical application prospects in alleviating the burden of both primary tumors and metastatic disease. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases non-receptor type (PTPNs) have been studied extensively in the context of the adaptive immune system; however, their roles beyond immunoregulation are less well explored. Here we identify novel functions for the conserved C. elegans phosphatase PTPN-22, establishing its role in nematode molting, cell adhesion, and cytoskeletal regulation. Through a non-biased genetic screen, we found that loss of PTPN-22 phosphatase activity suppressed molting defects caused by loss-of-function mutations in the conserved NIMA-related kinases NEKL-2 (human NEK8/NEK9) and NEKL-3 (human NEK6/NEK7), which act at the interface of membrane trafficking and actin regulation. To better understand the functions of PTPN-22, we carried out proximity labeling studies to identify candidate interactors of PTPN-22 during development. Through this approach we identified the CDC42 guanine-nucleotide exchange factor DNBP-1 (human DNMBP) as an in vivo partner of PTPN-22. Consistent with this interaction, loss of DNBP-1 also suppressed nekl-associated molting defects. Genetic analysis, co-localization studies, and proximity labeling revealed roles for PTPN-22 in several epidermal adhesion complexes, including C. elegans hemidesmosomes, suggesting that PTPN-22 plays a broad role in maintaining the structural integrity of tissues. Localization and proximity labeling also implicated PTPN-22 in functions connected to nucleocytoplasmic transport and mRNA regulation, particularly within the germline, as nearly one-third of proteins identified by PTPN-22 proximity labeling are known P granule components. Collectively, these studies highlight the utility of combined genetic and proteomic approaches for identifying novel gene functions. Author summary: The human protein, PTPN22, has been studied extensively within the context of the adaptive immune system and mutations that affect PTPN22 function are implicated in multiple autoimmune disorders. Curiously, PTPN22 is conserved throughout the animal kingdom, including in the invertebrate roundworm Caenorhabditis elegans, which lack an adaptive immune system. Using several non-biased approaches to uncover novel protein functions, we identified roles for the Caenorhabditis elegans PTPN22 ortholog, PTPN-22, in a several different cell biological processes including functions related to epithelial cell and tissue connectivity. These studies, along with our analysis of the cellular and subcellular locations in which PTPN-22 is present during development, indicate that the worm PTPN-22 carries out a diverse range of functions. Our studies indicate that, in addition to critical roles within the immune-system, PTPN22 family members may carry additional functions that are conserved throughout the animal kingdom, a finding supported by several studies carried out on human PTPN22 suggesting roles in cell-cell adhesion. [ABSTRACT FROM AUTHOR]

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes. PTPN2 (protein tyrosine phosphatase non-receptor type 2) and PTPN1 are attractive immuno-oncology targets, however, targeting PTPN2/N1 poses significant challenges. Here, the authors report the development of potent PTPN2/N1 heterobifunctional degraders and reveal biochemical and structural insights into the formation of ternary structures with cereblon E3 ligase by X-ray diffraction, cryo-EM and MD simulations. [ABSTRACT FROM AUTHOR]

Introduction: The early transcription unit 3 (E3) of human adenoviruses (HAdVs) encodes several immunoevasins, including the E3/49K protein, which is unique for species D of HAdVs. It is expressed as surface transmembrane protein and shed. E3/49K of HAdV-D64 binds to the protein tyrosine phosphatase surface receptor CD45, thereby modulating activation of T and NK cells. Methods: Considering that E3/49K represents the most polymorphic viral protein among species D HAdVs, we demonstrate here that all tested E3/49K orthologs bind to the immunologically important regulator CD45. Thus, this feature is conserved regardless of the pathological associations of the respective HAdV types. Results: It appeared that modulation of CD45 is a unique property restricted to HAdVs of species D. Moreover, E3/49K treatment inhibited B cell receptor (BCR) signaling and impaired BCR signal phenotypes. The latter were highly comparable to B cells having defects in the expression of CD45, suggesting E3/49K as a potential tool to investigate CD45 specific functions. Conclusion: We identified B cells as new direct target of E3/49K-mediated immune modulation, representing a novel viral immunosubversive mechanism. [ABSTRACT FROM AUTHOR]

Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input‐output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to NaV1.2 sodium channels, facilitating NEDD4L‐mediated ubiquitination, and endocytosis of NaV1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented NaV1.2‐mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno‐associated virus‐mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage‐gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of NaV1.2 channels' function. [ABSTRACT FROM AUTHOR]

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC 50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t 1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the "tunnel" allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC 50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer. Pyrazolopyrazine-based TK-642 is identified as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC 50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5 %; t 1/2 = 2.47 h). [Display omitted] [ABSTRACT FROM AUTHOR]

The neuroendocrine marker genes Ptprn and Ptprn2 encode protein tyrosine phosphatase receptors N and N2, 2 members of protein tyrosine phosphatase receptors void of enzymatic activity, and whose function and mechanism of action have not been elucidated. To explore the role(s) of Ptprn and Ptprn2 on the hypothalamic-pituitary-adrenal axis, we used mice in which both genes were knocked out (DKO). The focus in this study was on corticotrophs and melanotrophs from the anterior and intermediate lobes of the pituitary gland, respectively. In both sexes, DKO caused an increase in the expression of the corticotroph/melanotroph genes Pomc and Tbx19 and the melanotroph-specific gene Pax7. We also found in vivo and in vitro increased synthesis and release of beta-endorphin, alpha-melanocyte-stimulating hormone, and ACTH in DKO mice, which was associated with increased serum corticosterone levels and adrenal mass. DKO also increased the expression of other melanotroph-specific genes, but not corticotroph-specific genes. The dopaminergic pathway in the hypothalamus and dopaminergic receptors in melanotrophs were not affected in DKO mice. However, hyperplasia of the intermediate lobe was observed in DKO females and males, accompanied by increased proopiomelanocortin immunoreactivity per cell. These results indicate that protein tyrosine phosphatase receptor type N contributes to hypothalamic-pituitary-adrenal function by being involved in processes governing postnatal melanotroph development and Pomc expression. [ABSTRACT FROM AUTHOR]

Objective: Aruncus dioicus has been known by the scientific literature and folk experiences for its diverse biological activities, including anti-hyperglycemic effects. Methodology: The aerial parts of the plant collected from Quan Lan Island (Vietnam) were subjected to a methodical theory-experiment investigation for its chemical composition and biological potentials. Results: Firstly, experimental isolation and spectroscopic characterization identified the compositional compounds, ie sambunigrin (1), prunasin (2), uridine (3), and adenosine (4). Secondly, their elucidated structures were predicted with promising bio-chemo-pharmacological potentiality by different computational platforms, ie: docking simulation (docking scores < 10 kcal.mol−1); quantum calculation (dipole moments < 3 Debye); QSARIS model (satisfying Lipinski's rule of five); SwissADME model (satisfying Pires’ interpretations). Finally, the compounds (1-4) were under accumulative purification and in vitro tests against diabetes-related enzymes, ie: protein tyrosine phosphatase 1B (1 with lowest IC50 value 0.39 ± 0.26 μM, 2 with no activity) and α-glucosidase (1 with lowest IC50 value 44.89 ± 0.93 μM, 2 with no activity); also, the inhibitory kinetics based on Lineweaver-Burk and Dixon plot experiments revealed the competitive inhibition mode of 1 against PTP1B (Ki value 0.49 μM). Conclusions: Altogether, the results obtained suggest that A. dioicus and its bioactive compounds, especially sambunigrin (1), uridine (3), and adenosine (4), could be considered as a natural source for further research and development of anti-diabetic agents. [ABSTRACT FROM AUTHOR]

Mutations in the tyrosine phosphatase Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting autoinhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8 to 10 A from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine-binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein--protein interaction specificity that alters enzyme activation. [ABSTRACT FROM AUTHOR]

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by Ptpn6) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Ptpn6 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Ptpn6 (Shp1-Tg) and their wild type (WT) littermates were used. Ptpn6 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Ptpn6 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Ptpn6 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG. [ABSTRACT FROM AUTHOR]

PTPRK is a receptor tyrosine phosphatase that is linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell–cell contact. PTPRK regulates cell–cell adhesion but is also reported to regulate numerous cancer-associated signalling pathways. However, the signalling mechanism of PTPRK remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients. [ABSTRACT FROM AUTHOR]

The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) plays an important role in modulating glucose and lipid homeostasis. We previously suggested a potential role of SHP-1 in the regulation of peroxisome proliferator-activated receptor γ2 (PPARγ2) expression and activity but the mechanisms were unexplored. PPARγ2 is the master regulator of adipogenesis, but how its activity is regulated by tyrosine phosphorylation is largely unknown. Here, we found that SHP-1 binds to PPARγ2 primarily via its N-terminal SH2-domain. We confirmed the phosphorylation of PPARγ2 on tyrosine-residue 78 (Y78), which was reduced by SHP-1 in vitro resulting in decreased PPARγ2 stability. Loss of SHP-1 led to elevated, agonist-induced expression of the classical PPARγ2 targets FABP4 and CD36, concomitant with increased lipid content in cells expressing PPARγ2, an effect blunted by abrogation of PPARγ2 phosphorylation. Collectively, we discovered that SHP-1 affects the stability of PPARγ2 through dephosphorylation thereby influencing adipogenesis. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase—a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase non‐receptor type 21 (PTPN21) is a cytosolic protein tyrosine phosphatase that regulates cell growth and invasion. Due to its oncogenic properties, PTPN21 has recently emerged as a potential therapeutic target for cancer. In this study, the three‐dimensional structure of the PTPN21 FERM domain was determined at 2.1 Å resolution by X‐ray crystallography. The crystal structure showed that this domain harbors canonical FERM folding and consists of three subdomains that are tightly packed via highly conserved intramolecular hydrophobic interactions. Consistent with this, the PTPN21 FERM domain shares high structural homology with several other FERM domains. Moreover, structural superimposition demonstrated two putative protein‐binding sites of the PTPN21 FERM domain, which are presumed to be associated with interaction with its binding partner, kinesin family member 1C. Thus, these data suggest that the FERM domain of PTPN21 serves as a module that mediates protein–protein interaction, like other FERM domains. [ABSTRACT FROM AUTHOR]

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients. SHP2 interacts with ACK1 kinase to erase pY54-H3 (Tyr54-phosphorylation of histones H3) epigenetic marks and triggers Androgen receptor transcriptional program. It explains genital abnormalities and infertility in LEOPARD syndrome patients, and AR upregulation in prostate cancer. [ABSTRACT FROM AUTHOR]

Neutrophils are rapidly recruited to sites of infection and are critical for pathogen clearance. Therapeutic use of primary neutrophils has been limited, as they have a short lifespan and are not amenable to genetic manipulation. Human induced pluripotent stem cells (iPSCs) can provide a robust source of neutrophils for infusion and are genetically tractable. However, current work has indicated that dampened intracellular signaling limits iPSC-derived neutrophil (iNeutrophil) cellular activation and antimicrobial response. Here, we show that protein tyrosine phosphatase 1B (PTP1B) inhibits intracellular signaling and dampens iNeutrophil effector function. Deletion of the PTP1B phosphatase increased PI3K and ERK signaling and was associated with increased F-actin polymerization, cell migration, and phagocytosis. In contrast, other effector functions like NETosis and reactive oxygen species production were reduced. PTP1B-deficient neutrophils were more responsive to Aspergillus fumigatus and displayed rapid recruitment and control of hyphal growth. Accordingly, depletion of PTP1B increased production of inflammatory factors including the neutrophil chemokine interleukin-8. Taken together, these findings suggest that PTP1B limits iNeutrophil motility and antimicrobial function. [ABSTRACT FROM AUTHOR]