keyword
https://read.qxmd.com/read/38474536/cancer-related-mutations-in-the-sam-domains-of-epha2-receptor-and-ship2-lipid-phosphatase-a-computational-study
#1
JOURNAL ARTICLE
Marian Vincenzi, Flavia Anna Mercurio, Ida Autiero, Marilisa Leone
The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)-Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2-Sam and Ship2-Sam reciprocal binding interfaces...
February 27, 2024: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38409699/metformin-effects-on-ship2-ampks-and-gut-microbiota-recent-updates-on-pharmacology
#2
JOURNAL ARTICLE
Priyanka Shivaprakash, Narasimha M Beeraka, Subba Rao V Madhunapantula, Vladimir N Nikolenko, Kanthesh M Basalingappa
INTRODUCTION: Metformin, a biguanide on the WHO's list of essential medicines has a long history of 50 years or more in treating hyperglycemia, and its therapeutic saga continues beyond diabetes treatment. Glucoregulatory actions are central to the physiological effects of metformin; surprisingly, the precise mechanism with which metformin regulates glucose metabolism is not thoroughly understood yet. METHOD: The main aim of this review is to explore the recent implications of metformin in hepatic gluconeogenesis, AMPKs, and SHIP2 and subsequently to elucidate the metformin action across intestine and gut microbiota...
February 21, 2024: Current Medicinal Chemistry
https://read.qxmd.com/read/38309262/regulation-of-inositol-5-phosphatase-activity-by-the-c2-domain-of-ship1-and-ship2
#3
JOURNAL ARTICLE
William J Bradshaw, Emma C Kennedy, Tiago Moreira, Luke A Smith, Rod Chalk, Vittorio L Katis, Justin L P Benesch, Paul E Brennan, Emma J Murphy, Opher Gileadi
SHIP1, an inositol 5-phosphatase, plays a central role in cellular signaling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics on SHIP1 and SHIP2...
February 1, 2024: Structure
https://read.qxmd.com/read/38200519/phb2-promotes-ship2-ubiquitination-via-the-e3-ligase-nedd4-to-regulate-akt-signaling-in-gastric-cancer
#4
JOURNAL ARTICLE
Liang Xu, Wanying Xiang, Jiezhen Yang, Jing Gao, Xinyue Wang, Li Meng, Kaihong Ye, Xiao Hong Zhao, Xu Dong Zhang, Lei Jin, Yan Ye
BACKGROUND: Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC). METHODS: PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan-Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272)...
January 11, 2024: Journal of Experimental & Clinical Cancer Research: CR
https://read.qxmd.com/read/38141770/actin-binding-protein-profilin1-is-an-important-determinant-of-cellular-phosphoinositide-control
#5
JOURNAL ARTICLE
Morgan M C Ricci, Andrew Orenberg, Lee Ohayon, David Gau, Rachel C Wills, Yongho Bae, Tuhin Das, David Koes, Gerald R V Hammond, Partha Roy
Membrane poly-phosphoinositides (PPIs) are lipid-signaling molecules that undergo metabolic turnover and influence a diverse range of cellular functions. PPIs regulate the activity and/or spatial localization of a number of actin-binding proteins (ABPs) through direct interactions; however, it is much less clear whether ABPs could also be an integral part in regulating PPI signaling. In this study, we show that ABP profilin1 (Pfn1) is an important molecular determinant of cellular content of PI(4,5)P2 (the most abundant PPI in cells)...
December 21, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/38138538/structure-activity-studies-on-bis-sulfonamide-ship1-activators
#6
JOURNAL ARTICLE
Shea T Meyer, Sandra Fernandes, Robert E Anderson, Angela Pacherille, Bonnie Toms, William G Kerr, John D Chisholm
The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer's disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1...
December 12, 2023: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/38023622/ship1-therapeutic-target-enablement-identification-and-evaluation-of-inhibitors-for-the-treatment-of-late-onset-alzheimer-s-disease
#7
JOURNAL ARTICLE
Cynthia D Jesudason, Emily R Mason, Shaoyou Chu, Adrian L Oblak, June Javens-Wolfe, Mustapha Moussaif, Greg Durst, Philip Hipskind, Daniel E Beck, Jiajun Dong, Ovini Amarasinghe, Zhong-Yin Zhang, Adam K Hamdani, Kratika Singhal, Andrew D Mesecar, Sarah Souza, Marlene Jacobson, Jerry Di Salvo, Disha M Soni, Murugesh Kandasamy, Andrea R Masters, Sara K Quinney, Suzanne Doolen, Hasi Huhe, Stacey J Sukoff Rizzo, Bruce T Lamb, Alan D Palkowitz, Timothy I Richardson
INTRODUCTION: The risk of developing Alzheimer's disease is associated with genes involved in microglial function. Inositol polyphosphate-5-phosphatase ( INPP5D ), which encodes Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is a risk gene expressed in microglia. Because SHIP1 binds receptor immunoreceptor tyrosine-based inhibitory motifs (ITIMs), competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P2 , it is a negative regulator of microglia function...
2023: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://read.qxmd.com/read/37916396/sh2-domain-containing-inositol-5-phosphatases-support-the-survival-of-burkitt-lymphoma-cells-by-promoting-energy-metabolism
#8
JOURNAL ARTICLE
Florian Mayr, Vanessa Kruse, Dominik C Fuhrmann, Sebastian Wolf, Jens Löber, Saed Alsouri, Nadia Paglilla, Kwang Lee, Björn Chapuy, Bernhard Brüne, Thorsten Zenz, Björn Häupl, Thomas Oellerich, Michael Engelke
Burkitt lymphoma cells (BL) exploit antigen-independent tonic signals transduced by the B cell antigen receptor (BCR) for their survival, but the molecular details of the rewired BLspecific BCR signal network remain unclear. A loss of function screen revealed the SH2 domain-containing 5`-inositol phosphatase 2 (SHIP2) as a potential modulator of BL fitness. We characterized the role of SHIP2 in BL survival in several BL cell models and show that perturbing SHIP2 function renders cells more susceptible to apoptosis, while attenuating proliferation in a BCR-dependent manner...
November 2, 2023: Haematologica
https://read.qxmd.com/read/37103835/the-role-of-c2-domains-in-two-different-phosphatases-pten-and-ship2
#9
JOURNAL ARTICLE
Laura H John, Fiona B Naughton, Mark S P Sansom, Andreas Haahr Larsen
Phosphatase and tensin homologue (PTEN) and SH2-containing inositol 5'-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a phosphatase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P3 ; PTEN at the 3-phophate and SHIP2 at the 5-phosphate. Therefore, they play pivotal roles in the PI3K/Akt pathway. Here, we investigate the role of the C2 domain in membrane interactions of PTEN and SHIP2, using molecular dynamics simulations and free energy calculations...
April 4, 2023: Membranes
https://read.qxmd.com/read/36818285/obesity-control-by-ship-inhibition-requires-pan-paralog-inhibition-and-an-intact-eosinophil-compartment
#10
JOURNAL ARTICLE
Sandra Fernandes, Neetu Srivastava, Chiara Pedicone, Raki Sudan, Elizabeth A Luke, Otto M Dungan, Angela Pacherille, Shea T Meyer, Shawn Dormann, Stéphane Schurmans, Benedict J Chambers, John D Chisholm, William G Kerr
Here we extend the understanding of how chemical inhibition of SHIP paralogs controls obesity. We compare different classes of SHIP inhibitors and find that selective inhibitors of SHIP1 or SHIP2 are unable to prevent weight gain and body fat accumulation during increased caloric intake. Surprisingly, only pan-SHIP1/2 inhibitors (pan-SHIPi) prevent diet-induced obesity. We confirm that pan-SHIPi is essential by showing that dual treatment with SHIP1 and SHIP2 selective inhibitors reduced adiposity during excess caloric intake...
February 17, 2023: IScience
https://read.qxmd.com/read/36500543/-n1-benzyl-tryptamine-pan-ship1-2-inhibitors-synthesis-and-preliminary-biological-evaluation-as-anti-tumor-agents
#11
JOURNAL ARTICLE
Sandra Fernandes, Shea T Meyer, Jigisha P Shah, Arijit A Adhikari, William G Kerr, John D Chisholm
Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines...
December 2, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36402914/preterm-birth-alters-the-feeding-induced-activation-of-akt-signaling-in-the-muscle-of-neonatal-piglets
#12
JOURNAL ARTICLE
Agus Suryawan, Marko Rudar, Jane K Naberhuis, Marta L Fiorotto, Teresa A Davis
BACKGROUND: Postnatal lean mass accretion is commonly reduced in preterm infants. This study investigated mechanisms involved in the blunted feeding-induced activation of Akt in the skeletal muscle of preterm pigs that contributes to lower protein synthesis rates. METHODS: On day 3 following cesarean section, preterm and term piglets were fasted or fed an enteral meal. Activation of Akt signaling pathways in skeletal muscle was determined. RESULTS: Akt1 and Akt2, but not Akt3, phosphorylation were lower in the skeletal muscle of preterm than in term pigs (P < 0...
November 19, 2022: Pediatric Research
https://read.qxmd.com/read/36344496/linc01468-drives-nafld-hcc-progression-through-cul4a-linked-degradation-of-ship2
#13
JOURNAL ARTICLE
Hongquan Wang, Yan Wang, Shihui Lai, Liang Zhao, Wenhui Liu, Shiqian Liu, Haiqiang Chen, Jinhua Wang, Guanhua Du, Bo Tang
Accumulating evidence suggests that long noncoding RNAs (lncRNAs) are deregulated in hepatocellular carcinoma (HCC) and play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the current understanding of the role of lncRNAs in NAFLD-associated HCC is limited. In this study, transcriptomic profiling analysis of three paired human liver samples from patients with NAFLD-driven HCC and adjacent samples showed that LINC01468 expression was significantly upregulated. In vitro and in vivo gain- and loss-of-function experiments showed that LINC01468 promotes the proliferation of HCC cells through lipogenesis...
November 7, 2022: Cell Death Discovery
https://read.qxmd.com/read/36232599/structural-insights-into-the-binding-propensity-of-human-ship2-sh2-to-oncogenic-caga-isoforms-from-helicobacter-pylori
#14
JOURNAL ARTICLE
Zi Wang, Yubao Shan, Ru Wang, Heng Zhou, Rui Hu, Ying Li, Jiang Zhu, Yunhuang Yang, Maili Liu
SHIP2 is a multi-domain inositol 5-phosphatase binding to a variety of phosphotyrosine (pY)-containing proteins through its SH2 domain, so as to regulate various cell signaling pathways by modulating the phosphatidylinositol level in the plasma membrane. Unfavorably, Helicobacter pylori can hijack SHIP2 through the CagA protein to induce gastric cell carcinogenesis. To date, the interaction between SHIP2 and CagA was not analyzed from a structural point of view. Here, the binding of SHIP2-SH2 with Tyr-phosphorylated peptides from four EPIYA motifs (A/B/C/D) in CagA was studied using NMR spectroscopy...
September 25, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36142306/hunting-for-novel-routes-in-anticancer-drug-discovery-peptides-against-sam-sam-interactions
#15
REVIEW
Flavia Anna Mercurio, Marian Vincenzi, Marilisa Leone
Among the diverse protein binding modules, Sam (Sterile alpha motif) domains attract attention due to their versatility. They are present in different organisms and play many functions in physiological and pathological processes by binding multiple partners. The EphA2 receptor contains a Sam domain at the C-terminus (EphA2-Sam) that is able to engage protein regulators of receptor stability (including the lipid phosphatase Ship2 and the adaptor Odin). Ship2 and Odin are recruited by EphA2-Sam through heterotypic Sam-Sam interactions...
September 8, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/35832491/cell-dependent-pathogenic-roles-of-filamin-b-in-different-skeletal-malformations
#16
JOURNAL ARTICLE
Huixiao Wu, Yanzhou Wang, Xinyu Chen, Yangyang Yao, Wanyi Zhao, Li Fang, Xiaoqing Sun, Ning Wang, Jie Jiang, Ling Gao, Jiajun Zhao, Chao Xu
Mutations of filamin B ( FLNB ) gene can lead to a spectrum of autosomal skeletal malformations including spondylocarpotarsal syndrome (SCT), Larsen syndrome (LRS), type I atelosteogenesis (AO1), type III atelosteogenesis (AO3), and boomerang dysplasia (BD). Among them, LRS is milder while BD causes a more severe phenotype. However, the molecular mechanism underlying the differences in clinical phenotypes of different FLNB variants has not been fully determined. Here, we presented two patients suffering from autosomal dominant LRS and autosomal recessive vitamin D-dependent rickets type IA (VDDR-IA)...
2022: Oxidative Medicine and Cellular Longevity
https://read.qxmd.com/read/35465359/discovery-of-a-novel-ship1-agonist-that-promotes-degradation-of-lipid-laden-phagocytic-cargo-by-microglia
#17
JOURNAL ARTICLE
Chiara Pedicone, Sandra Fernandes, Alessandro Matera, Shea T Meyer, Stewart Loh, Jeung-Hoi Ha, Denzil Bernard, John D Chisholm, Rosa Chiara Paolicelli, William G Kerr
Here, we describe the use of artificial intelligence to identify novel agonists of the SH2-containing 5' inositol phosphatase 1 (SHIP1). One of the compounds, K306, represents the most potent agonist identified to date. We find that K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2, and this activation does not require the C2 domain of SHIP1 which other known SHIP1 agonists require. Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. Importantly, we find that K306 can suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts...
April 15, 2022: IScience
https://read.qxmd.com/read/35454152/cell-culture-media-unlike-the-presence-of-insulin-affect-%C3%AE-synuclein-aggregation-in-dopaminergic-neurons
#18
JOURNAL ARTICLE
Irena Hlushchuk, Justyna Barut, Mikko Airavaara, Kelvin Luk, Andrii Domanskyi, Piotr Chmielarz
There are several links between insulin resistance and neurodegenerative disorders such as Parkinson's disease. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation-a hallmark of Parkinson's disease-remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological α-synuclein accumulation induced by the addition of α-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect α-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor...
April 9, 2022: Biomolecules
https://read.qxmd.com/read/35421738/oxldl-stimulated-macrophage-exosomes-promote-proatherogenic-vascular-smooth-muscle-cell-viability-and-invasion-via-delivering-mir-186-5p-then-inactivating-ship2-mediated-pi3k-akt-mtor-pathway
#19
JOURNAL ARTICLE
Lingyun Ren, Shanshan Chen, Dan Yao, Hong Yan
The current study aimed to investigate the implication of microRNA (miRNA) profile in the linkage between oxidized low-density-lipoprotein (oxLDL)-stimulated-macrophages (MФ) exosomes and vascular smooth muscle cells (VSMCs) during atherosclerosis. VSMCs were treated by oxLDL-stimulated-MФ with/without GW4869. MiRNA profile in oxLDL-stimulated-MФ and untreated-MФ was detected by microarray, then candidate miRNAs were proposed to RT-qPCR and functional validation in VSMCs. MiR-186-5p mimic/inhibitor was transfected into oxLDL-stimulated-MФ, then its exosomes were used to VSMCs...
April 11, 2022: Molecular Immunology
https://read.qxmd.com/read/35381186/computational-studies-of-the-principle-of-dynamic-change-driven-protein-interactions
#20
JOURNAL ARTICLE
Zhen-Lu Li, Carla Mattos, Matthias Buck
Dynamic allostery emphasizes a role of entropy change manifested as a sole change in protein fluctuations without structural changes. This kind of entropy-driven effect remains largely understudied. The most significant examples involve protein-ligand interactions, leaving protein-protein interactions, which are critical in signaling and other cellular events, largely unexplored. Here we study an example of how protein-protein interaction (binding of Ras to the Ras binding domain [RBD] of the effector protein Raf) affects a subsequent protein association process (Ras dimerization) by quenching Ras internal motions through dynamic allostery...
June 2, 2022: Structure
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