scholarly journals A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

2018 ◽  
Author(s):  
Taylor L. Mighell ◽  
Sara Evans-Dutson ◽  
Brian j. O’Roak
Keyword(s):  
Phosphatase Activity ◽  
Autism Spectrum ◽  
Saturation Mutagenesis ◽  
Single Amino Acid ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Functional Scores

ABSTRACTPhosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16×10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.

scholarly journals Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianyu He ◽  
Xiaoyun Zhang ◽  
Jianyu Hao ◽  
Shigang Ding
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Malignant Tumors ◽  
Biological Effects ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
And Migration

The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Mi Tian ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Mrna ◽  
Normal Chow ◽  
Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

In silico approach of naringin as potent phosphatase and tensin homolog (PTEN) protein agonist against prostate cancer

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Sankar Muthumanickam ◽  
Thangamariyappan Indhumathi ◽  
Pandi Boomi ◽  
Ramachandran Balajee ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Silico ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

2019 ◽  
Vol 316 (1) ◽  
pp. H61-H69 ◽  
Author(s):  
Wenbo Yang ◽  
Zhijun Wu ◽  
Ke Yang ◽  
Yanxin Han ◽  
Yanjia Chen ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
B Lymphoma ◽  
Tensin Homolog ◽  
And Migration ◽  
Proliferation And Migration

Cardiac fibrosis has been known to play an important role in the etiology of heart failure after myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region 1 wk post-MI in mice and was detected by Western blot and histological analyses. Lentivirus-mediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 wk after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro , whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 wk post-MI in vivo. Furthermore, upregulated BMI1 inhibited phosphatase and tensin homolog (PTEN) expression, enhanced phosphatidylinositol 3-kinase (PI3K) expression, and increased the phosphorylation level of Akt and mammalian target of rapamycin (mTOR) in mice 4 wk after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual-kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction after MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/Akt-mTOR pathway. NEW & NOTEWORTHY Ischemia-induced B lymphoma Mo-MLV insertion region 1 homolog (BMI1) significantly promoted cardiac fibrosis and worsened cardiac function in vivo, whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in myocardial infarcted mice. BMI1 also enhanced proliferation and migration capabilities of fibroblasts in vitro; these effects were reversed by NVP-BEZ235. Effects of BMI1 on cardiac fibrosis could be partially explained by regulation of the phosphatase and tensin homolog-phosphatidylinositol 3-kinase/Akt-mammalian target of rapamycin pathway.

Reduced PTEN Protein Expression and Its Prognostic Implications in Canine and Feline Mammary Tumors

2009 ◽  
Vol 46 (5) ◽  
pp. 860-868 ◽  
Author(s):  
L. Ressel ◽  
F. Millanta ◽  
E. Caleri ◽  
V. M. Innocenti ◽  
A. Poli
Keyword(s):  
Protein Expression ◽  
Lymphatic Vessel ◽  
Mammary Tumors ◽  
Lymphatic Vessel Invasion ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Mammary Carcinomas ◽  
Tensin Homolog ◽  
Vessel Invasion ◽  
Distant Organ

Phosphatase and tensin homolog (PTEN) belongs to the group of gatekeeper tumor suppressor genes and is involved in multiple mechanisms leading to cellular defense against neoplastic transformation and progression. Twenty-four dogs and 17 cats were submitted to a 2-year follow-up study, and clinicopathologic features were recorded and compared with immunohistochemical PTEN staining. PTEN-negative status occurred in 33% of canine and 76% of feline mammary carcinomas. In canine mammary carcinomas, there was a significant ( P < .05) correlation between loss of PTEN protein expression and simple carcinoma histotype, lymphatic vessel invasion, lymph node metastases, distant organ metastases, tumor dedifferentiation, tumor recurrence, and shorter overall survival. In feline mammary tumors, a significant correlation between loss of PTEN protein expression and lymphatic vessel invasion was found. Loss of PTEN expression could be a useful prognostic marker in canine mammary carcinomas.

scholarly journals Induction of Apoptotic Genes by a p73-Phosphatase and Tensin Homolog (p73-PTEN) Protein Complex in Response to Genotoxic Stress

2011 ◽  
Vol 286 (42) ◽  
pp. 36631-36640 ◽  
Author(s):  
Jason A. Lehman ◽  
David L. Waning ◽  
Christopher N. Batuello ◽  
Rocky Cipriano ◽  
Madhavi P. Kadakia ◽  
...  
Keyword(s):  
Protein Complex ◽  
Genotoxic Stress ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Apoptotic Genes

scholarly journals Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis

2017 ◽  
Vol 114 (18) ◽  
pp. E3709-E3718 ◽  
Author(s):  
Subhash Kulkarni ◽  
Maria-Adelaide Micci ◽  
Jenna Leser ◽  
Changsik Shin ◽  
Shiue-Cheng Tang ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Dynamic Balance ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Enteric Neurons ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Myenteric Ganglia

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

scholarly journals Podocyte-specific knockin of PTEN protects kidney from hyperglycemia

2018 ◽  
Vol 314 (6) ◽  
pp. F1096-F1107 ◽  
Author(s):  
Huizhen Wang ◽  
Ziwei Feng ◽  
Jianteng Xie ◽  
Feng Wen ◽  
Menglei Jv ◽  
...  
Keyword(s):  
Diabetic Kidney Disease ◽  
Therapeutic Strategy ◽  
Renal Protection ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Matrix Expansion ◽  
Interfering Rna

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

scholarly journals Molecular Analysis of AFP and HSA Interactions with PTEN Protein

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mingyue Zhu ◽  
Bo Lin ◽  
Peng Zhou ◽  
Mengsen Li
Keyword(s):  
Molecular Docking ◽  
Molecular Mechanisms ◽  
Docking Study ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Docking Study ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Significant Homology ◽  
Modeling Data

Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN.In siliconsubstitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

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