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Darren J Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L Zenner, Wenjun Bie, Angela L Tyner
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342...
November 15, 2017: Nature Communications
Águeda González-Rodríguez, M Pilar Valdecantos, Patricia Rada, Annalisa Addante, Inés Barahona, Esther Rey, Virginia Pardo, Laura Ruiz, Laura M Laiglesia, María J Moreno-Aliaga, Carmelo García-Monzón, Aránzazu Sánchez, Ángela M Valverde
OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). METHODS: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks...
October 31, 2017: Molecular Metabolism
Samantha Le Sommer, Nicola Morrice, Martina Pesaresi, Dawn Thompson, Mark A Vickers, Graeme I Murray, Nimesh Mody, Benjamin G Neel, Kendra K Bence, Heather M Wilson, Mirela Delibegovic
Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia (AML). LysM-PTP1B-/- mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells...
November 9, 2017: Cancer Research
Wen-Long Wang, Xiao-Yu Chen, Ya Gao, Li-Xin Gao, Li Sheng, Jingyu Zhu, Lei Xu, Zhen-Zhong Ding, Chao Zhang, Jing-Ya Li, Jia Li, Yu-Bo Zhou
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC50 of 2...
October 26, 2017: Bioorganic & Medicinal Chemistry Letters
Jason Hon, Michelle S Hwang, Meara A Charnetzki, Issra J Rashed, Patrick B Brady, Sarah Quillin, Marvin W Makinen
Protein tyrosine phosphatases (PTPases) are a prominent focus of drug design studies because of their roles in homeostasis and disorders of metabolism. These studies have met with little success because (1) virtually all inhibitors hitherto exhibit only competitive behavior and (2) a consensus sequence H/V-C-X5-R-S/T characterizes the active sites of PTPases, leading to low specificity of active site directed inhibitors. With protein tyrosine phosphatase-1B (PTP1B) identifed as the target enzyme of the vanadyl (VO(2+)) chelate bis(acetylacetonato)oxidovanadium(IV) [VO(acac)2] in 3T3-L1 adipocytes [Ou et al...
December 2017: Journal of Biological Inorganic Chemistry: JBIC
Pedro Geraldes
PURPOSE OF REVIEW: Deregulation of protecting factor signaling actions in podocytes has emerged as an alternative pathway of podocyte injury mechanisms. Here, we review recent knowledge that highlighted how podocyte protecting factors are modulated by protein phosphatases. RECENT FINDINGS: Protein tyrosine kinases and phosphatases participate in many, if not all, aspects of cellular function by turning on or off multiple signaling cascades and podocytes are no exception...
October 23, 2017: Current Opinion in Nephrology and Hypertension
Juan Xiong, Jiang Wan, Jie Ding, Pei-Pei Wang, Guang-Lei Ma, Jia Li, Jin-Feng Hu
Seven new naturally occurring barrigenol-like compounds, camellianols A-G (1-7), and 10 known triterpenoids were isolated from the twigs and leaves of the cultivated endangered ornamental plant Camellia crapnelliana. According to the ECD octant rule for saturated cyclohexanones, the absolute configurations of camellianols D (4) and E (5) were defined. The backbones of the remaining new isolates are assumed to have the same absolute configuration as compounds 4, 5, and harpullone (12). Compounds 2, 3, 9, 10, 13, and 16 exhibited inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme, with IC50 values less than 10 μM...
October 24, 2017: Journal of Natural Products
Jiao Luo, Qi Xu, Bo Jiang, Renshuai Zhang, Xiaoling Jia, Xiangqian Li, Lijun Wang, Chuanlong Guo, Ning Wu, Dayong Shi
BACKGROUND AND PURPOSE: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor. It is a highly validated target for type 2 diabetes therapeutics. Here, the anti-diabetic effects of HPN were evaluated in the diabetic BKS db mice. EXPERIMENTAL APPROACH: The inhibitory mode of PTP1B was determined according to the Lineweaver-Burk plot in the presence of HPN. Surface plasmon resonance (SPR) assay and molecular docking were used to study the interaction between HPN and PTP1B...
October 23, 2017: British Journal of Pharmacology
Shi-Jun Yue, Juan Liu, Wu-Wen Feng, Fei-Long Zhang, Jian-Xin Chen, Lan-Ting Xin, Cheng Peng, Hua-Shi Guan, Chang-Yun Wang, Dan Yan
The rapidly increasing diabetes mellitus (DM) is becoming a major global public health issue. Traditional Chinese medicine (TCM) has a long history of the treatment of DM with good efficacy. Huangqi and Huanglian are one of the most frequently prescribed herbs for DM, and the combination of them occurs frequently in antidiabetic formulae. However, the synergistic mechanism of Huangqi (Radix Astragali) and Huanglian (Rhizoma Coptidis) has not been clearly elucidated. To address this problem, a feasible system pharmacology model based on chemical, pharmacokinetic and pharmacological data was developed via network construction approach to clarify the synergistic mechanisms of these two herbs...
2017: Frontiers in Pharmacology
Fangfang Yan, Xinguo Liu, Shaolong Zhang, Jing Su, Qinggang Zhang, Jianzhong Chen
Endocellular protein tyrosine phosphatase 1B (PTP1B) is one of the most promising target for designing and developing drugs to cure type-II diabetes and obesity. Molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) methods were applied to study binding differences of three inhibitors (ID: 901, 941 and 968) to PTP1B, the calculated results show that the inhibitor 901 has the strongest binding ability to PTP1B among the current inhibitors...
October 19, 2017: Journal of Biomolecular Structure & Dynamics
Da Hye Kim, Pradeep Paudel, Ting Yu, Thi Men Ngo, Jeong Ah Kim, Hyun Ah Jung, Takako Yokozawa, Jae Sue Choi
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator that plays an important role in many signaling pathways, especially those associated with insulin resistance. In this study, we investigated the anti-diabetic potential of 12 natural tanshinones isolated from Salvia miltiorrhiza (S. miltiorrhiza) Bunge (Lamiaceae), deoxyneocryptotanshinone (1), grandifolia F (2), ferruginol (3), cryptotanshinone (4), tanshinone IIA (5), tanshinol B (6), tanshinone IIB (7), tanshinonal (8), methyl tanshinonate (9), 15,16-dihydrotanshinone I (10), tanshinone I (11), and dehydrodanshenol A (12) and evaluated their inhibitory activity against PTP1B...
October 12, 2017: Chemico-biological Interactions
Himanshu Kumar Bhakta, Pradeep Paudel, Hajime Fujii, Atsuya Sato, Chan Hum Park, Takako Yokozawa, Hyun Ah Jung, Jae Sue Choi
Insulin resistance and protein tyrosine phosphatase 1B (PTP1B) overexpression are strongly associated with type 2 diabetes mellitus (T2DM), which is characterized by defects in insulin signaling and glucose intolerance. In a previous study, we demonstrated oligonol inhibits PTP1B and α-glucosidase related to T2DM. In this study, we examined the molecular mechanisms underlying the anti-diabetic effects of oligonol in insulin-resistant HepG2 cells. Glucose uptake was assessed using a fluorescent glucose tracer, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and the signaling pathway was investigated by western blotting...
October 12, 2017: Archives of Pharmacal Research
Stefan Wagner, Matteo Accorsi, Jörg Rademann
α,α-Difluoro-benzyl phosphonates are currently the most popular class of phosphotyrosine mimetics. Structurally derived from the natural substrate phosphotyrosine, they constitute classical bioisosteres and have enabled the development of potent inhibitors of protein tyrosine phosphatases (PTP) and phosphotyrosine recognition sites such as SH2 domains. Being dianions bearing two negative charges, phosphonates, however, do not permeate membranes and thus are often inactive in cells and have not been a successful starting point toward therapeutics, yet...
October 11, 2017: Chemistry: a European Journal
Ya-Nan Wang, Ling-Yan Wang, Yu-Hong Qu, Ming Jiang, Yu-Zhuo Wu, Rui Li, Bo-Lin Qiu, Su-Juan Wang, Sheng Lin
A new styrene dimer derivative has been isolated from the branch of Litsea greenmaniana by column chromatography over silica gel and Sephadex LH-20, as well as semi-preparative HPLC. Its structure was identified by spectroscopic data analysis (MS, UV, IR, 1D and 2D NMR) as (E)-2,4-bis(p-hydroxyphenyl)-2-butenol, named as listeanol. At a concentration of 1×10-5 mol•L⁻¹, compound 1 was inactive in the assays, including cytotoxicity against human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549 and A2780), antioxidant activity in Fe²⁺-cystine-induced rat liver microsomal lipid peroxidation, neuroprotective activity against serum deprivation or glutamate induced neurotoxicity in cultures of PC12 cells, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B)...
March 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Yue Zhou, Yun-Hai Li, Hao-Bing Yu, Xiao-Yu Liu, Xiao-Ling Lu, Bing-Hua Jiao
A new furanone derivative, butanolide A (1), and a new sesquiterpene, guignarderemophilane F (2), together with six known compounds, were isolated from the fungus Penicillium sp. S-1-18 derived from Antarctic marine. The new structures were determined by spectroscopic studies such as 1D- and 2D-NMR and MS analyses. The absolute configuration of 1 was determined by the modified Mosher's method, while the absolute configuration of 2 was determined by calculated ECD spectroscopy. The isolated secondary metabolites were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activity...
October 9, 2017: Journal of Asian Natural Products Research
Hao Wang, Xiaoxu Sun, Ning Zhang, Zhouye Ji, Zhanqiang Ma, Qiang Fu, Rong Qu, Shiping Ma
Cognitive impairment has been recognized as a typical characteristic of neurodegenerative disease in diabetes mellitus (DM) and this cognitive dysfunction may be a risk factor for Alzheimer's disease (AD). Ferulic acid, a phenolic compound commonly found in a range of plants, has emerged various properties including anti-inflammatory and neuroprotective effects. In the present study, the protective activities and relevant mechanisms of ferulic acid were evaluated in diabetic rats with cognitive deficits, which were induced by a high-glucose-fat (HGF) diet and low dose of streptozotocin (STZ)...
December 1, 2017: Physiology & Behavior
Yoshihiro Ito, Ming-Fo Hsu, Ahmed Bettaieb, Shinichiro Koike, Aline Mello, Miguel Calvo-Rubio, Jose M Villalba, Fawaz G Haj
OBJECTIVE: Diabetic nephropathy is one of the most devastating complications of diabetes, and growing evidence implicates podocyte dysfunction in disease pathogenesis. The objective of this study was to investigate the contribution of protein tyrosine phosphatase 1B (PTP1B) in podocytes to hyperglycemia-induced renal injury. METHODS: To determine the in vivo function of PTP1B in podocytes we generated mice with podocyte-specific PTP1B disruption (hereafter termed pod-PTP1B KO)...
November 2017: Metabolism: Clinical and Experimental
Junfei Zhou, Na Sun, Hanqi Zhang, Guijuan Zheng, Junjun Liu, Guangmin Yao
Three novel diterpenoids with an unprecedented 2,3:5,6-di-seco-grayanane carbon skeleton, rhodomollacetals A-C (1-3), are isolated from the leaves of Rhododendron molle. Their structures are elucidated by comprehensive spectroscopic techniques and single-crystal X-ray diffraction. Rhodomollacetal A (1) possesses a novel cis/cis/cis/cis-fused 6/6/6/6/5 pentacyclic ring system, featuring an unprecedented 11,13,18-trioxa-pentacyclo [,8).0(2,8).0(12,17)]nonadecane scaffold. Compounds 2 and 3 have a rare 4-oxatricyclo[7...
October 6, 2017: Organic Letters
Jun Li Yang, Thi Kim Quy Ha, Ba Wool Lee, Jinwoong Kim, Won Keun Oh
To find PTP1B inhibitors from natural products, two new compounds (1 and 2), along with nine known compounds (3-11), were isolated from a methanol-soluble extract of Iris sanguinea seeds. The structures of compounds 1 and 2 were determined based on extensive spectroscopic data analysis including UV, IR, NMR, and MS. The IC50 value of compound 5 on protein tyrosine phosphatase 1B (PTP1B) inhibitory activity is 7.30±0.88µM with a little activity compared to the IC50 values of the tested positive compound. Compound 5 significantly enhanced glucose uptake and activation of pACC, pAMPK and partially Erk1/2 signaling...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
Kelly Barford, Austin Keeler, Christopher Deppmann, Bettina Winckler
In neurons, correct targeting of receptors to the axon is critical for cell survival and circuit formation. In this issue of Developmental Cell, Yamashita et al. (2017) report that the ER-resident phosphatase PTP1B is required to prime TrkA for axonal transport.
September 25, 2017: Developmental Cell
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