PTPN11 Research Articles

Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 μM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 μM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 μM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

Spongia Sponges: Unabated Sources of Novel Secondary Metabolites.

Marine sponges of the genus Spongia have proven to be unabated sources of novel secondary metabolites with remarkable scaffold diversities and significant bioactivities. The discovery of chemical substances from Spongia sponges has continued to increase over the last few years. The current work provides an up-to-date literature survey and comprehensive insight into the reported metabolites from the members of the genus Spongia, as well as their structural features, biological activities, and structure-activity relationships when available. In this review, 222 metabolites are discussed based on published data from the period from mid-2015 to the beginning of 2024. The compounds are categorized into sesquiterpenes, diterpenes, sesterterpenes, meroterpenes, linear furanoterpenes, steroids, alkaloids, and other miscellaneous substances. The biological effects of these chemical compositions on a vast array of pharmacological assays including cytotoxic, anti-inflammatory, antibacterial, neuroprotective, protein tyrosine phosphatase 1B (PTP1B)-inhibitory, and phytoregulating activities are also presented.

Elucidating the structural basis of vitamin B12 derivatives as novel potent inhibitors of PTP1B: Insights from inhibitory mechanisms using Gaussian accelerated molecular dynamics (GaMD) and in vitro study

Vitamin B12 is a group of biologically active cobalamin compounds. In this study, we investigated the inhibitory effects of methylcobalamin (MeCbl) and hydroxocobalamin acetate (OHCbl Acetate) on protein tyrosine phosphatase 1B (PTP1B). MeCbl and OHCbl Acetate exhibited an IC50 of approximately 58.390 ± 2.811 μM and 8.998 ± 0.587 μM, respectively. The Ki values of MeCbl and OHCbl Acetate were 25.01 μM and 4.04 μM respectively. To elucidate the inhibition mechanism, we conducted a 500 ns Gaussian accelerated molecular dynamics (GaMD) simulation. Utilizing PCA and tICA, we constructed Markov state models (MSM) to examine secondary structure changes during motion. Our findings revealed that the α-helix at residues 37–42 remained the most stable in the PTP1B-OHCbl Acetate system. Furthermore, upon binding of OHCbl Acetate or MeCbl, the WPD loop of PTP1B moved inward to the active pocket, forming a closed conformation and potentially obstructs substrate entry. Protein-ligand interaction analysis and MM-PBSA showed that OHCbl Acetate exhibited lower binding free energy and engaged in more residue interactions with PTP1B. In summary, our study confirmed the substantial inhibitory activity of OHCbl Acetate against PTP1B, with its inhibitory potency notably surpassing that of MeCbl. We demonstrated potential molecular mechanisms of OHCbl Acetate inhibiting PTP1B.

Assessment of genetic markers associated with the development of bronchopulmonary dysplasia in premature infants in the structure of a prognostic model of its development

Introduction. Bronchopulmonary dysplasia (BPD) is a complex disease with a significant genetic predisposition. The aim of the study was to determine genetic markers associated with the development of bronchopulmonary dysplasia in premature infants. 
 Materials and methods. At Stage 1, whole exome sequencing followed by the bioinformatic analysis of one hundred samples was provided to evaluate the genetic variants. Sequencing data were compared with the data of the children without any congenital pulmonary diseases. At Stage 2, the obtained results were validated using real-time PCR. Further the genotyping of the control group (n = 70) was performed. The obtained frequencies of nucleotide variants were compared between the groups, as well as with general population data using the RUSeq database. 
 Results. The prevalence of genetic variant rs12489516 in gene CPA3 was significantly higher in the control group of premature infants (p = 0.03; OR = 0.2; 95% CI: 0.02–0.94). Its presence in the genotype reduces the likelihood of developing BPD by 4.76 times. Moreover, statistically significant differences were also identified in the prevalence of rs45488997 in gene CCN2 (p = 0.023). This genetic variant was specific only for children with bronchopulmonary dysplasia. It was also identified that the prevalence of the nucleotide variant rs45488997 in the CCN2 gene was statistically more common among patients with bronchopulmonary dysplasia compared with the general population (p = 0.005). In addition, genetic variants rs5744174 in gene TLR5 and rs2476601 in gene PTPN22 were less frequently observed in the investigated group compared to the general population (p = 0.03 and p = 0.003, respectively). 
 Conclusion. Identification of genetic markers together with clinical and laboratory data will contribute to the development of an effective predictive model for the calculation of the probability of BPD.

Noonan syndrome: molecular and clinical findings in individuals with PTPN11 pathogenic variants

Purpose: RASopathies encompass a spectrum of disorders resulting from pathogenic variants in genes associated with the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway, critical for cellular functions like proliferation, differentiation and survival. Noonan syndrome (NS), the most prevalent form of RASopathies, presents with a myriad of clinical features including characteristic facial dysmorphisms, congenital heart defects, and developmental delays. Despite its clinical recognition, molecular confirmation remains elusive in a notable percentage of cases. In this study, we aimed to investigate the clinical and molecular profiles of six patients diagnosed with NS, focusing on the role of PTPN11 gene mutations. Materials and methods: Molecular evaluation was performed using PTPN11 gene sequence analysis and whole gene sequencing methods in six patients who were thought to have typical NS phenotypes based on clinical evaluations. Results: Molecular screening in patients identified four different pathogenic variants in the PTPN11 gene. These variants, all heterozygous, were classified as pathogenic according to established criteria. Conclusion: Our findings contribute to understanding the genetic landscape of NS and underscore the significance of molecular analysis in confirming diagnoses.

Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity.

Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship. The screened analogues S2, S6, A2-14, A2-17, A2-20, and A2-21 exhibited an improved PTP1B/TC-PTP dual inhibitory activity and achieved good stability in the plasma of mice and dogs, which indicated long-acting potential. In mouse models of type 2 diabetes mellitus (T2DM), the selected analogues S6, S7, A2-20, and A2-21 with an excellent target activity and plasma stability generated once-weekly therapeutic potency for T2DM at lower dosage (0.5 μmol/kg). In addition, evidence was provided to confirm the cell permeability and targeted enrichment of the BimBH3 analogues. In summary, we report here that site-specific modification and long fatty acid conjugation afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced stability, in vivo activity, and long-acting pharmacokinetic profile. Our findings could guide the further optimization of BimBH3 analogues and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new therapeutic approach for T2DM, which may facilitate the discovery and development of alternative once-weekly anti-T2DM drug candidates.

Recent Advances in Grayanane Diterpenes: Isolation, Structural Diversity, and Bioactivities from Ericaceae Family (2018-2024).

Diterpenes represent one of the most diverse and structurally complex families of natural products. Among the myriad of diterpenoids, grayanane diterpenes are particularly notable. These terpenes are characterized by their unique 5/7/6/5 tetracyclic system and are exclusive to the Ericaceae family of plants. Renowned for their complex structures and broad spectrum of bioactivities, grayanane diterpenes have become a primary focus in extensive phytochemical and pharmacological research. Recent studies, spanning from 2018 to January 2024, have reported a series of new grayanane diterpenes with unprecedented carbon skeletons. These compounds exhibit various biological properties, including analgesic, antifeedant, anti-inflammatory, and inhibition of protein tyrosine phosphatase 1B (PTP1B). This paper delves into the discovery of 193 newly identified grayanoids, representing 15 distinct carbon skeletons within the Ericaceae family. The study of grayanane diterpenes is not only a deep dive into the complexities of natural product chemistry but also an investigation into potential therapeutic applications. Their unique structures and diverse biological actions make them promising candidates for drug discovery and medicinal applications. The review encompasses their occurrence, distribution, structural features, and biological activities, providing invaluable insights for future pharmacological explorations and research.

Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays.

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer's disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases' treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 μM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food-medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.

Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation.

Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V+ procoagulant endothelial CD62E+ (E-selectin) and neutrophil (Ly6G+) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.

Pachymic acid exerts antitumor activities by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B

Objective: To determine the inhibitory effects of pachymic acid on lung adenocarcinoma (LUAD) cells and elucidate its underlying mechanism. Methods: CCK-8, wound healing, Transwell, Western blot, tube formation, and immunofluorescence assays were carried out to measure the effects of various concentrations of pachymic acid on LUAD cell proliferation, metastasis, angiogenesis as well as autophagy. Subsequently, molecular docking technology was used to detect the potential targeted binding association between pachymic acid and protein tyrosine phosphatase 1B (PTP1B). Moreover, PTP1B was overexpressed in A549 cells to detect the specific mechanisms of pachymic acid. Results: Pachymic acid suppressed LUAD cell viability, metastasis as well as angiogenesis while inducing cell autophagy. It also targeted PTP1B and lowered PTP1B expression. However, PTP1B overexpression reversed the effects of pachymic acid on metastasis, angiogenesis, and autophagy as well as the expression of Wnt3a and β-catenin in LUAD cells. Conclusions: Pachymic acid inhibits metastasis and angiogenesis, and promotes autophagy in LUAD cells by modulating the Wnt/β-catenin signaling pathway via targeting PTP1B.

In silico Analysis of Selected Four-Leaf Water Clover (Marsilea species) Constituents as Human Acetyl Cholinesterase (hAchE), Carbonic Anhydrase II (hCA-II), and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitory Agents

ABSTRACT A four-leaf water clover (Marsilea species) has been reported to exhibit various biological activities. In the present study, we aimed to evaluate 23 selected constituents of a four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B) using an in silico method. The 23 selected constituents of the four-leaf water clover (Marsilea species) were studied on the docking behavior of hAchE, hCA-II, and hPTP-1B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM web server. Toxicity analysis has shown that 10 ligands (44%) of the four-leaf water clover (Marsilea species) were predicted to have hERG II (human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that marsilin has exhibited the maximum binding energy (-11.3 kcal/mol) with the hAchE, whereas it fails to dock with both the target enzymes (hCA-II and hPTP-1B). Thus, the present find provides a new understanding about the 23 selected ligands of the four-leaf water clover (Marsilea species) as potent inhibitory agents of human acetyl cholinesterase (hAchE), carbonic anhydrase II (hCA-II), and protein tyrosine phosphatase 1B (hPTP-1B).

A fast and efficient method for screening and evaluation of hypoglycemic ingredients of Traditional Chinese Medicine acting on PTP1B by capillary electrophoresis

As a pivotal enzyme that regulates dephosphorylation in cell activities and participates in the insulin signaling pathway, protein tyrosine phosphatase 1B (PTP1B) is considered to be an important target for the therapy of diabetes. In this work, a rapid and efficient inhibitor screening method of PTP1B was established based on capillary electrophoresis (CE), and used for screening and evaluating the inhibition effect of Traditional Chinese Medicine on PTP1B. Response Surface Methodology was used for optimizing the conditions of analysis. After method validation, the enzyme kinetic study and inhibition test were performed. As a result, the IC50 of PTP1B inhibitors Ⅳ and ⅩⅧ were consistent with reported values measured by a conventional method. It was found that the extracts of Astragalus membranaceus (Fisch) Bunge and Morus alba L. showed prominent inhibition on the activity of PTP1B, which were stronger than the positive controls. Meanwhile, on top of the excellent advantages of CE, the whole analysis time is less than 2 min. Thus, the results demonstrated that a fast and efficient screening method was successfully developed. This method could be a powerful tool for screening inhibitors from complex systems. It can also provide an effective basis for lead compound development in drug discovery.

Unveiling Anti-Diabetic Potential of Baicalin and Baicalein from Baikal Skullcap: LC-MS, In Silico, and In Vitro Studies.

Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography-mass spectrometry (LC-MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.

Protein tyrosine phosphatase 1B in metabolic diseases and drug development.

Proteintyrosine phosphatase 1B (PTP1B), a non-transmembrane phosphatase, has a major role in a variety of signalling pathways, including direct negative regulation of classic insulin and leptin signalling pathways, and is implicated in the pathogenesis of several cardiometabolic diseases and cancers. As such, PTP1B has been a therapeutic target for over two decades, with PTP1B inhibitors identified either from natural sources or developed throughout the years. Some of these inhibitors have reached phase I and/or II clinical trials in humans for the treatment of type 2 diabetes mellitus, obesity and/or metastatic breast cancer. In this Review, we summarize the cellular processes and regulation of PTP1B, discuss evidence from in vivo preclinical and human studies of the association between PTP1B and different disorders, and discuss outcomes of clinical trials. We outline challenges associated with the targeting of this phosphatase (which was, until the past few years, viewed as difficult to target), the current state of the field of PTP1B inhibitors (and dual phosphatase inhibitors) and future directions for manipulating the activity of this key metabolic enzyme.

Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity.

The 1858C>T allele of the tyrosine phosphatase PTPN22 is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in anti-viral immunity remains poorly defined. Here, we use single cell RNA-sequencing and functional studies to interrogate the impact of this pro-autoimmune allele on anti-viral immunity during Lymphocytic Choriomeningitis Virus clone 13 (LCMV-cl13) infection. Mice homozygous for this allele (PEP-619WW) clear the LCMV-cl13 virus whereas wildtype (PEP-WT) mice cannot. This is associated with enhanced anti-viral CD4 T cell responses and a more immunostimulatory CD8α- cDC phenotype. Adoptive transfer studies demonstrated that PEP-619WW enhanced anti-viral CD4 T cell function through virus-specific CD4 T cell intrinsic and extrinsic mechanisms. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a beneficial anti-viral immune response thereby preventing what is normally a chronic virus infection.

Shared and distinct genetics of pure type 1 diabetes and type 1 diabetes with celiac disease, homology in their auto-antigens and immune dysregulation states: a study from North India.

This study was undertaken to explicate the shared and distinctive genetic susceptibility and immune dysfunction in patients with T1D alone and T1D with CD (T1D + CD). A total of 100 T1D, 50 T1D + CD and 150 healthy controls were recruited. HLA-DRB1/DQB1 alleles were determined by PCR-sequence-specific primer method, SNP genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP-array and genotyping for INS-23 Hph1 A/T was done by RFLP. Autoantibodies and cytokine estimation was done by ELISA. Immune-regulation was analysed by flow-cytometry. Clustering of autoantigen epitopes was done by epitope cluster analytical tool. Both T1D alone and T1D + CD had a shared association of DRB1*03:01, DRB1*04, DRB3*01:07/15 and DQB1*02. DRB3*01:07/15 confers the highest risk for T1D with relative risk of 11.32 (5.74-22.31). Non-HLA gene polymorphisms PTPN22 and INS could discriminate between T1D and T1D + CD. T1D + CD have significantly higher titers of autoantibodies, expression of costimulatory molecules on CD4 and CD8 cells, and cytokine IL-17A and TGF-β1 levels compared to T1D patients. Epitopes from immunodominant regions of autoantigens of T1D and CD clustered together with 40% homology. Same HLA genes provide susceptibility for both T1D and CD. Non-HLA genes CTLA4, PTPN22 and INS provide further susceptibility while different polymorphisms in PTPN22 and INS can discriminate between T1D and T1D + CD. Epitope homology between autoantigens of two diseases further encourages the two diseases to occur together. The T1D + CD being more common in females along with co-existence of thyroid autoimmunity, and have more immune dysregulated state than T1D alone.

Spectrum of Mutations in PTPN11 in Russian Cohort.

Noonan syndrome is a group of diseases with a similar clinical picture, consisting of 16 diseases caused by mutations in 15 genes. According to the literature, approximately half of all cases are attributed to Noonan syndrome type 1, NSML, caused by mutations in the PTPN11 gene. We analyzed 456 unrelated probands using a gene panel NGS, and in 206 cases, the cause of the disease was identified. Approximately half of the cases (107) were caused by variants in the PTPN11 gene, including three previously undescribed variants, one of which was classified as VOUS, and the other two as LP causative complex alleles. Frequent variants of the PTPN11 gene characteristics for Russian patients were identified, accounting for more than 38% (c.922A>G p.Asn308Asp, c.417G>C p.Glu139Asp, c.1403C>T p.Thr468Met) of all cases with mutations in the PTPN11 gene. A comparative characterization of frequent variants of the PTPN11 gene in different populations is shown. The most common features of Noonan syndrome in the studied sample were facial dysmorphisms and cardiovascular system abnormalities. A lower representation of patients with growth delay was observed compared to previously described samples.

Switching photocurrent polarity and mimicking enzyme functions of MIL-53(Fe)@hemin for homogeneous dual-modal ultrasensitive detection of PTP1B

Protein tyrosine phosphatase 1B (PTP1B) as a regulatory enzyme is an important target for the early diagnosis and drug discovery of diabetes, obesity, and cancer. Herein, a homogeneous dual-modal biosensor integrating photoelectrochemical and colorimetric (PEC-CL) strategies was developed in light of the switching photocurrent polarity and mimicking enzyme functions of MIL-53(Fe)@hemin for the sensitive detection of PTP1B activity. Magnetic Fe3O4@Au NPs were synthesized for more sufficient homogeneous biorecognition, and modified with the phosphorylated peptides (p-Peptide), and sequentially connected with MIL-53(Fe)@hemin by the specific coordination of phosphate groups with Fe(III). After PTP1B-mediated specific recognition and dephosphorylation, the separated MIL-53(Fe)@hemin were quickly collected via magnetic separation for further PEC and CL assay. MIL-53(Fe)@hemin not only switched the photocurrent polarity of SnS2 NFs from anode to cathode, but also exhibited excellent peroxidase-like activity for oxidizing 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of H2O2. As a signal amplifier, MIL-53(Fe) acted as a nanocarrier to load abundant PEC signal switching factor of hemin, and synergistically enhanced its enzyme-mimic property. Consequently, ultrasensitive PEC biosensing (with linear response range of 0.1 pg mL−1 to 3000 ng mL−1 and detection limit of 0.074 pg mL−1) assisted by visual CL strategy (with linear response range of 10 pg mL−1 to 3000 ng mL−1 and detection limit of 0.24 pg mL−1) for PTP1B activity assay were achieved, which not only provided high sensitivity, but also possessed portability, perceptual intuition and reliability.

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.