Protein tyrosine phosphatase non-receptor type 12 suppresses tumor progression in osteosarcoma cells.

BACKGROUND: Protein tyrosine phosphatase non-receptor 12 (PTPN12) plays a prominent role in various cancers as a tumor suppressor. However, the expression of PTPN12 and its biological functions in osteosarcoma (OS) remains to be determined. METHODS: PTPN12 expression in OS was explored in public databases and detected by immunohistochemistry and Western blot. The cell viability was determined by Cell Counting Kit-8 (CCK-8) assay and colony formation. The cell migration and invasion were assessed by the Transwell assay. Flow cytometry analysis was applied to detect cell apoptosis and cell cycle distribution. To investigate the related mechanism, the levels of EGFR and downstream proteins were detected by Western blot. RESULTS: PTPN12 expression was significantly decreased in OS samples in GEO database and our hospital. OS cell lines in Cancer Cell Line Encyclopedia (CCLE) database and our cultured OS cells also demonstrated low PTPN12 expression. Lentivirus-induced overexpression of PTPN12 significantly inhibited the cell viability, migration and invasion of 143B and U2OS cells. The results of flow cytometry found that PTPN12 overexpression promoted cell apoptosis and induced cell cycle arrest at G1 phase in 143B and U2OS cells. The phosphorylation levels of EGFR and subsequent proteins of the PI3K/AKT and ERK pathways were inactivated as a result of PTPN12 overexpression in OS. CONCLUSION: PTPN12 plays a tumor suppressive role in OS cells. Restoring of PTPN12 activity may provide new insights for the treatment of this disease.

LncRNA GATA2-AS1 suppresses esophageal squamous cell carcinoma progression via the mir-940/PTPN12 axis.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor worldwide. Long noncoding RNAs (lncRNAs) exhibit a regulatory role in the progression of ESCC. Our research was performed to investigate the potential molecular mechanism of lncRNA GATA2-AS1 in ESCC. METHODS: The expression of GATA2-AS1 was identified by qRT-PCR. Cell function assays explored the potential effect of GATA2-AS1 on ESCC progression. The subcellular hierarchical localization method was executed to identify the subcellular localization of GATA2-AS1 in ESCC cells. A prediction website was utilized to discover the relationships among GATA2-AS1, miR-940 and PTPN12. Dual luciferase reporter gene, pull-down assays and RIP assays were executed to verify the binding activity among GATA2-AS1, miR-940 and PTPN12. Xenograft tumor experiments were performed to evaluate ESCC cell growth in vivo. RESULTS: The expression of GATA2-AS1 and PTPN12 was reduced, while miR-940 expression was enhanced in ESCC tissues and cell lines. In vivo experiments showed that GATA2-AS1 inhibited the progression of ESCC cells toward malignancy. Bioinformatics analysis, dual luciferase and RIP assays revealed that GATA2-AS1 upregulated PTPN12 expression by competitively targeting miR-940. miR-940 reversed the inhibitory effect of GATA2-AS1 on the biological behavior of ESCC cells. CONCLUSION: Our findings suggested that GATA2-AS1, expressed at low levels in ESCC, plays a crucial role in the progression of ESCC by targeting the miR-940/PTPN12 axis and could be a potential drug target to treat ESCC patients.

SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding.

The kinase Csk is the primary negative regulator of the Src-family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes), phosphorylating a tyrosine on the SFK C-terminal tail that mediates autoinhibition. Csk also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (LYP/Pep), which dephosphorylate the SFK activation loop to promote autoinhibition. Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains, and high local concentration promotes Csk function. Purified Csk homodimerizes in solution through an interface that overlaps the phosphatase binding footprint. Here we demonstrate that Csk can homodimerize in Jurkat T cells, in competition with PTPN22 binding. We designed SH3-domain mutations in Csk that selectively impair homodimerization (H21I) or PTPN22 binding (K43D) and verified their kinase activity in solution. Disruption of either interaction in cells, however, decreased the negative-regulatory function of Csk. Csk W47A, a substitution previously reported to block PTPN22 binding, had a secondary effect of impairing homodimerization. Csk H21I and K43D will be useful tools for dissecting the protein-specific drivers of autoimmunity mediated by the human polymorphism PTPN22 R620W, which impairs interaction with Csk and with the E3 ubiquitin ligase TRAF3. Future investigations of Csk homodimer activity and phosphatase interactions may reveal new facets of SFK regulation in hematopoietic and non-hematopoietic cells.

Protein tyrosine phosphatase non-receptor type 12 (PTPN12), negatively regulated by miR-106a-5p, suppresses the progression of hepatocellular carcinoma.

Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is abnormally expressed in many human cancers. However, its role in hepatocellular carcinoma (HCC) is indeterminate. In this study, immunohistochemistry and Western blot were adopted to detect PTPN12 protein expression in HCC tissues and cell lines. MiR-106a-5p and PTPN12 mRNA expressions were determined by quantitative real-time polymerase chain reaction (qRT-PCR). siRNA was used to knockdown PTPN12 expression in HCC cells, and the multiplication, migration, and invasion of HCC cells were determined by cell counting kit 8 (CCK-8) and Transwell assays. The interaction between PTPN12 and miR-106a-5p was verified by dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. In the present study, we demonstrated that PTPN12 expression in HCC tissues and cells was significantly decreased, which was associated with the tumor size, TNM stage, and lymph node metastasis of HCC patients. Functionally, knocking down PTPN12 significantly promoted the multiplication, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. PTPN12 was identified as the direct target of miR-106a-5p, and its expression was negatively modulated by miR-106a-5p. Besides, PTPN12 counteracted the promoting effects of miR-106a-5p on the viability, migration, invasion, and EMT of HCC cells. In conclusion, this study substantiates that PTPN12 inhibits the growth, migration, invasion, and EMT of HCC cells, and miR-106a-5p contributes to its dysregulation in HCC.

Evaluating Large Spontaneous Deletions in a Bovine Cell Line Selected for Bovine Viral Diarrhea Virus Resistance.

Bovine viral diarrhea virus's (BVDV) entry into bovine cells involves attachment of virions to cellular receptors, internalization, and pH-dependent fusion with endosomal membranes. The primary host receptor for BVDV is CD46; however, the complete set of host factors required for virus entry is unknown. The Madin-Darby bovine kidney (MDBK) cell line is susceptible to BVDV infection, while a derivative cell line (CRIB) is resistant at the level of virus entry. We performed complete genome sequencing of each to identify genomic variation underlying the resistant phenotype with the aim of identifying host factors essential for BVDV entry. Three large compound deletions in the BVDV-resistant CRIB cell line were identified and predicted to disrupt the function or expression of the genes PTPN12, GRID2, and RABGAP1L. However, CRISPR/Cas9 mediated knockout of these genes, individually or in combination, in the parental MDBK cell line did not impact virus entry or replication. Therefore, resistance to BVDV in the CRIB cell line is not due to the apparent spontaneous loss of PTPN12, GRID2, or RABGAP1L gene function. Identifying the functional cause of BVDV resistance in the CRIB cell line may require more detailed comparisons of the genomes and epigenomes.

Role of the F-BAR Family Member PSTPIP2 in Autoinflammatory Diseases.

Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) belongs to the Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain family. It exhibits lipid-binding, membrane deformation, and F-actin binding activity, suggesting broader roles at the membrane-cytoskeleton interface. PSTPIP2 is known to participate in macrophage activation, neutrophil migration, cytokine production, and osteoclast differentiation. In recent years, it has been observed to play important roles in innate immune diseases and autoinflammatory diseases (AIDs). Current research indicates that the protein tyrosine phosphatase PTP-PEST, Src homology domain-containing inositol 5'-phosphatase 1 (SHIP1), and C-terminal Src kinase (CSK) can bind to PSTPIP2 and inhibit the development of AIDs. However, the mechanisms underlying the function of PSTPIP2 have not been fully elucidated. This article reviews the research progress and mechanisms of PSTPIP2 in AIDs. PSTPIP2 also provides a new therapeutic target for the treatment of AIDs.

circPTPN12/miR-21-5 p/∆Np63α pathway contributes to human endometrial fibrosis.

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5 p to inhibit miR-21-5 p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT and administration of miR-21-5 p could reverse this process and improve endometrial fibrosis. Our findings revealed that the dysfunction of circPTPN12/miR-21-5 p/∆Np63α pathway contributed to the pathogenesis of endometrial fibrosis.

Expression and clinical significance of PTPN12 in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common urological disease. Expression of the protein tyrosine phosphatase 12 gene (PTPN12) is decreased in many cancers; however, the relationship between PTPN12 gene function and renal cancer remains unclear. METHODS: We detected PTPN12 protein expression in ccRCC and corresponding normal tissues from 64 patients with ccRCC by immunohistochemistry, and relative PTPN12 mRNA levels by real-time quantitative polymerase chain reaction. The relationships between the relative expression levels of PTPN12 mRNA and the patients' clinical data were analyzed. RESULTS: PTPN12 protein and mRNA expression levels were significantly lower in ccRCC compared with the corresponding normal tissues. The mRNA expression levels in the ccRCC and corresponding normal tissues from the 64 patients with ccRCC were 0.459±0.445 and 1.001±0.128, respectively, compared with the control (glyceraldehyde 3-phosphate dehydrogenase). There was a significant correlation between relative expression of PTPN12 mRNA in ccRCC tissues and tumor diameter and clinical stage. CONCLUSION: The expression levels of PTPN12 protein and mRNA were significantly lower in ccRCC tissues compared with normal tissues. The role of PTPN12 may provide new insights and evidence to aid the diagnosis and targeted therapy of ccRCC.

Nonreceptor protein tyrosine phosphatases (NRPTPs) gene family associates with the risk of hepatocellular carcinoma in a Chinese hepatitis B virus-related subjects.

Nonreceptor protein tyrosine phosphatases (NRPTPs) are reported to be associated with several human cancers, but their roles in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. Here, we integrated bioinformatics tools, population association analyses, and biological assays to systematically screen for potentially functional single nucleotide polymorphisms (SNPs) within the 17 NRPTPs genes and evaluate the effects of candidate SNPs on the risk of HCC or persistent HBV infection. A total of 790 HBV-related HCC cases and 1454 cancer-free controls were enrolled. Controls included 711 HBV persistent carriers and 743 spontaneously recovered subjects. Results demonstrated that PTPN4 rs9308777 (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.49, P = .009) and PTPN12 rs350050 (OR = 1.26, 95% CI = 1.10-1.45, P = .001), were significantly associated with HCC risk, but not with persistent HBV infection risk. The cumulative risk effect of these two SNPs was more significantly increased the susceptibility to HCC (OR = 1.27, 95% CI = 1.14-1.41, P = 2.40 × 10-5 ). Subsequent biological assays further revealed the potential pathogenesis that PTPN4 rs9308777 might decrease the gene expression, and PTPN12 rs3750050 might promote cell proliferation by attenuating PTPN12's inhibitory activity on EGFR/ERK pathway. In summary, our integrative study highlights that PTPN4 and PTPN12 are significantly associated with HBV-related HCC risk, but do not influence persistent HBV infection. These findings shed light on the importance of the synergistic effects of regulatory and missense variants on the risk for HCC, and provide data to support personalized cancer medicine in the future.

Progress in the correlation between PTPN12 gene expression and human tumors.

BACKGROUND: The global morbidity of cancer is rising rapidly. Despite advances in molecular biology, immunology, and cytotoxic and immune-anticancer therapies, cancer remains a major cause of death worldwide. Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a new member of the cytoplasmic protein tyrosine phosphatase family, isolated from a cDNA library of adult colon tissue. Thus far, no studies have reviewed the correlation between PTPN12 gene expression and human tumors. METHODS: This article summarizes the latest domestic and international research developments on how the expression of PTPN12 relates to human tumors. The extensive search in Web of Science and PubMed with the keywords including PTPN12, tumor, renal cell carcinoma, proto-oncogenes, tumor suppressor genes was undertaken. RESULTS: More and more studies have shown that a tumor is essentially a genetic disease, arising from a broken antagonistic function between proto-oncogenes and tumor suppressor genes. When their antagonistic effect is out of balance, it may cause uncontrolled growth of cells and lead to the occurrence of tumors. PTPN12 is a tumor suppressor gene, so inhibiting its activity will lead directly or indirectly to the occurrence of tumors. CONCLUSION: The etiology, prevention, and treatment of tumors have become the focus of research around the world. PTPN12 is a tumor suppressor gene. In the future, PTPN12 might serve as a novel molecular marker to benefit patients, and even the development of tumor suppressor gene activation agents can form a practical research direction.

Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction.

AIMS: The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes. METHODS AND RESULTS: Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function. CONCLUSIONS: PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.

A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling.

BACKGROUND: The classical protein tyrosine phosphatases (PTPs) have been widely reported to be associated with various human malignancies including colorectal cancer (CRC). However, there are few comprehensive analyses of the association between the classical PTP genes and CRC risk. METHODS: First, a bioinformatics analysis was performed to identify missense variants within the classical PTP gene family. Second, exome-wide association data and an independent population study were conducted to evaluate effects of candidate variants on CRC risk. Finally, functional assays based on signaling pathways were applied to uncover the potential pathogenic mechanism. RESULTS: We identified that PTPN12 rs3750050 G allele presented a 19% increase the risk of CRC, with an OR of 1.19 (95% CI = 1.09-1.30, P = 1.015×10-4) under an additive model in the combined analysis. Furthermore, biochemical assays illustrated that rs3750050 could impair the inhibitory effect of PTPN12 on Ras/MEK/ERK signaling by impeding SHC dephosphorylation, increase the expression of cyclin D1 and ultimately lead to aberrant cell proliferation, thus contributing to CRC pathogenesis. CONCLUSION: Our study highlights that PTPN12 rs3750050 could increase CRC risk by modifying Ras/MEK/ERK signaling. This work provides a novel insight into the roles of genetic variants within PTP genes in the pathogenesis of CRC.

Prognostic Value of Phosphotyrosine Phosphatases in Hepatocellular Carcinoma.

BACKGROUND/AIMS: During the occurrence and progression of hepatocellular carcinoma (HCC), phosphotyrosine phosphatases (PTPs) are usually described as tumor suppressors or proto-oncogenes, and to some degree are correlated with the prognosis of HCC. METHODS: A total of 321 patients from the Cancer Genome Atlas (TCGA) database and 180 patients from our validated cohort with hepatocellular carcinoma were recruited in this study. Kaplan-Meier, univariate and multivariate Cox proportional hazards model were used to evaluate the risk factors for survival. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were applied to detect the expression levels of PTP genes. RESULTS: After screening the data of TCGA, we identified five PTPs as HCC overall survival related PTP genes, among which only three (PTPN12, PTPRN, PTPN18) exhibited differential expression levels in our 180 paired HCC and adjacent tissues (P< 0.001). Further analysis revealed that expression of PTPN18 was positively, but PTPRN was negatively associated with prognosis of HCC both in TCGA cohort and our own cohort. As to PTPN12, results turned out to be opposite according to HBV status. In detail, higher expression of PTPN12 was associated with better outcome in HBV group but worse prognosis in Non-HBV group. CONCLUSION: Our results suggested that PTPN12, PTPRN and PTPN18 were independent prognostic factors in HCC.

PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells.

Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass, escaping surgical resection and invariably giving rise to lethal recurrent lesions. Here we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin-containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell-invasive growth in vitro and in preclinical mouse models. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.Significance: PTP-PEST balances GBM cell growth and invasion by interacting with the ATP-dependent ubiquitin segregase Vcp/p97 and regulating phosphorylation and stability of the focal adhesion protein p130Cas.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3809/F1.large.jpg Cancer Res; 78(14); 3809-22. ©2018 AACR.

PTPN12 Affects Nasopharyngeal Carcinoma Cell Proliferation and Migration Through Regulating EGFR.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) shows the leading morbidity in otorhinolaryngological malignant tumor. It is a common malignancy in China with obvious reginal distribution. NPC is a polygenic disease that is affected by numerous factors. Protein tyrosine phosphatase nonreceptor type 12 (PTPN12) regulates multiple tumor proliferation and development, including breast cancer and colon cancer. However, the role of PTPN12 in NPC occurrence and development has not been elucidated. PATIENTS AND METHODS: NPC cell line CNE2 was cultured in vitro and divided into three groups, including control, empty plasmid, and PTPN12 groups. PTPN12 mRNA and protein expressions were tested by real-time polymerase chain reaction and Western blot. CNE2 cell proliferation was detected by MTT assay. Cell migration was determined by wound healing assay. Cell apoptosis was evaluated by caspase 3 activity detection. Epidermal growth factor receptor (EGFR) expression was assessed by Western blot. RESULTS: PTPN12 plasmid transfection increased PTPN12 mRNA and protein expressions, suppressed cell proliferation and migration, reduced EGFR level, and enhanced caspase 3 activity compared with control and empty plasmid groups (p < 0.05). CONCLUSIONS: PTPN12 regulates NPC proliferation and migration through negative regulating EGFR. It could be treated as a molecular target for NPC diagnosis and prognosis analysis.

Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRß, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRß and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRß and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale for combining RTK inhibitors in TNBC and other malignancies that lack receptor-activating mutations.

Expression, purification and characterization of a catalytic domain of human protein tyrosine phosphatase non-receptor 12 (PTPN12) in Escherichia coli with FKBP-type PPIase as a chaperon.

Protein tyrosine phosphatase non-receptor type 12 (PTPN12), also known as PTP-PEST, was broadly expressed in hemopoietic cells. Recent research has shown that this enzyme is involved in tumorigenesis, as well as in tumor progression and transfer, as it can suppress multiple oncogenic tyrosine kinases. However, the difficulty of soluble expression of PTP-PEST in prokaryotic cells has resulted in great limitations in investigating its structure and functions. In this study, we successfully carried out soluble expression of the catalytic domain of PTP-PEST (ΔPTP-PEST) in Escherichia coli and performed an enzymatic characterization and kinetics. To confirm expression efficiency, we also induced the expression of the chaperon, FKBP_C. FKBP_C expression indicated efficacious prokaryotic expression of ΔPTP-PEST. In conclusion, our work yielded a practical expression system and two-step chromatography purification method that may serve as a valuable tool for the structural and functional analysis of proteins that are difficult to express in the soluble form in prokaryotic cells.

Structure and Molecular Dynamics Simulations of Protein Tyrosine Phosphatase Non-Receptor 12 Provide Insights into the Catalytic Mechanism of the Enzyme.

Protein tyrosine phosphatase non-receptor 12 (PTPN12) is an important protein tyrosine phosphatase involved in regulating cell adhesion and migration as well as tumorigenesis. Here, we solved a crystal structure of the native PTPN12 catalytic domain with the catalytic cysteine (residue 231) in dual conformation (phosphorylated and unphosphorylated). Combined with molecular dynamics simulation data, we concluded that those two conformations represent different states of the protein which are realized during the dephosphorylation reaction. Together with docking and mutagenesis data, our results provide a molecular basis for understanding the catalytic mechanism of PTPN12 and its role in tumorigenesis.

Update on enthesitis-related arthritis.

PURPOSE OF REVIEW: This review provides a detailed update regarding the genetics, pathogenesis, disease phenotype evaluation, therapies and expected outcomes for children with enthesitis-related arthritis (ERA). RECENT FINDINGS: Recent studies evaluated human leukocyte antigen (HLA)-B27 subtypes and non-major histocompatibility complex genes including toll like receptor 4, NLRP3, CXCR4 and PTPN12 in children with ERA. The microbiome and γδ-T cells have also been an area of active investigation. Several studies focus on the imaging phenotype of children with ERA, including the use of ultrasonography and MRI. MRI techniques studied in this population include dedicated MRI, whole-body MRI and diffusion-weighted imaging. Conventional and biologic disease-modifying agents continue to be the mainstay of therapy, though the past 2 years have witnessed several greatly needed randomized controlled trials to study the efficacy of these medications in ERA. Finally, long-term effectiveness studies of biologics in children with ERA have helped inform provider and patient expectations of disease response and prognosis. SUMMARY: Further evaluation of the role of the microbiome and the interleukin 17/interleukin 23 axis, techniques to optimize evaluation of disease features, and efficacy and effectiveness of newer medications are greatly needed in this understudied population of children.

Hepatitis B virus mutations, expression quantitative trait loci for PTPN12, and their interactions in hepatocellular carcinoma.

Previously we identified that HBV(Hepatitis B virus) sequence variation, which may interact with host human leukocyte antigen (HLA) genetic variation, could influence host risk of hepatocellular carcinoma (HCC). More HBV-host interactions need to be identified. Protein tyrosine phosphatase nonreceptor type 12 (PTPN12), serves as an antagonist to tyrosine kinase signaling, may play integral roles in immune response against HBV infection and the development of HCC. Rs11485985 was an expression quantitative trait loci (eQTL) for PTPN12 by bioinformatics analyses. In this study, we genotyped the PTPN12 eQTL and sequenced the HBV region EnhII/BCP/PC in a case-control cohort including 1507 HBV-related HCC cases and 1560 HBV persistent carriers as controls. The variant genotype GG of rs11489585 increased HCC risk compared to the HBV persistent carriers (adjusted OR = 2.03, 95% confidence interval [CIs] = 1.30-3.18). We also detected borderline significant associations of PTPN12 eQTL rs11489585 with HBV mutations (P = 0.05 for G1799C). Taken together, PTPN12 may influence HCC risk accompanied by HBV mutations.