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https://www.readbyqxmd.com/read/28636047/decoding-the-regulatory-mechanism-of-glucose-and-insulin-induced-phosphatidylinositol-3-4-5-trisphosphate-dynamics-in-%C3%AE-cells
#1
Tagari Samanta, Peeyush Sharma, Dwijendra Kukri, Sandip Kar
In MIN6 pancreatic β-cells, glucose and insulin act in a synergistic manner to regulate the dynamics of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). However, the precise regulatory mechanism behind such an experimentally observed synergy is poorly understood. In this article, we propose a phenomenological mathematical model for studying the glucose and insulin driven PIP3 activation dynamics under various stimulatory conditions to unfold the mechanism responsible for the observed synergy. The modeling study reveals that the experimentally observed oscillation in PIP3 dynamics with disparate time scales for different external glucose doses is mainly orchestrated by the complex dynamic regulation of cytosolic Ca(2+) in β-cells...
June 21, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28635959/optogenetic-activation-of-plexin-b1-reveals-contact-repulsion-between-osteoclasts-and-osteoblasts
#2
Abhijit Deb Roy, Taofei Yin, Shilpa Choudhary, Vladimir Rodionov, Carol C Pilbeam, Yi I Wu
During bone remodelling, osteoclasts induce chemotaxis of osteoblasts and yet maintain spatial segregation. We show that osteoclasts express the repulsive guidance factor Semaphorin 4D and induce contact inhibition of locomotion (CIL) in osteoblasts through its receptor Plexin-B1. To examine causality and elucidate how localized Plexin-B1 stimulation may spatiotemporally coordinate its downstream targets in guiding cell migration, we develop an optogenetic tool for Plexin-B1 designated optoPlexin. Precise optoPlexin activation at the leading edge of migrating osteoblasts readily induces local retraction and, unexpectedly, distal protrusions to steer cells away...
June 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28628306/lysine-deacetylation-by-hdac6-regulates-the-kinase-activity-of-akt-in-human-neural-progenitor-cells
#3
Jonathan Iaconelli, Jasmin Lalonde, Bradley Watmuff, Bangyan Liu, Ralph Mazitschek, Stephen J Haggarty, Rakesh Karmacharya
AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and β-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1)...
June 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28547571/clinical-presentations-and-molecular-studies-of-invasive-renal-epithelioid-angiomyolipoma
#4
Cheng-Keng Chuang, Hsin Chia Angela Lin, Han-Yu Tasi, Kun-Han Lee, Yuting Kao, Fukai Leo Chuang, Ying-Hsu Chang, Po-Hung Lin, Chung-Yi Liu, See-Tong Pang
PURPOSE: Epithelioid angiomyolipoma (EAML) is a rare variant of renal angiomyolipoma with malignant potential, and the cytogenetic and clinical behavior of EAML remains a challenging issue. METHODS: We retrospectively analyze the clinical courses of five EAML, the use of everolimus on metastatic EAML, and next-generation sequencing (NGS) and polymerase chain reaction (PCR) studies to investigate the gene mutation of TSC and the impact of PI3K/Akt/mTOR signaling pathway in metastatic EAML...
May 25, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28516764/an-autoinhibitory-role-for-the-pleckstrin-homology-domain-of-interleukin-2-inducible-tyrosine-kinase-and-its-interplay-with-canonical-phospholipid-recognition
#5
Sujan Devkota, Raji E Joseph, Scott E Boyken, D Bruce Fulton, Amy H Andreotti
Pleckstrin homology (PH) domains are well-known as phospholipid binding modules, yet evidence that PH domain function extends beyond lipid recognition is mounting. In this work, we characterize a protein binding function for the PH domain of interleukin-2-inducible tyrosine kinase (ITK), an immune cell specific signaling protein that belongs to the TEC family of nonreceptor tyrosine kinases. Its N-terminal PH domain is a well-characterized lipid binding module that localizes ITK to the membrane via phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding...
May 25, 2017: Biochemistry
https://www.readbyqxmd.com/read/28515318/molecular-mechanism-of-activation-of-class-ia-phosphoinositide-3-kinases-pi3ks-by-membrane-localized-hras
#6
Braden D Siempelkamp, Manoj K Rathinaswamy, Meredith L Jenkins, John E Burke
Class IA PI3Ks are involved in the generation of the key lipid signaling molecule phosphatidylinositol 3,4,5-trisphosphate (PIP3), and inappropriate activation of this pathway is implicated in a multitude of human diseases, including cancer, inflammation, and primary immunodeficiencies. Class IA PI3Ks are activated downstream of the Ras superfamily of GTPases, and Ras-PI3K interaction plays a key role in promoting tumor formation and maintenance in Ras-driven tumors. Investigating the detailed molecular events in the Ras-PI3K interaction has been challenging because it occurs on a membrane surface...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28450917/diagnostic-value-of-high-frequency-color-doppler-ultrasonography-examination-in-combination-with-anti-cyclic-citrullinated-peptide-antibody-testing-in-rheumatoid-arthritis-patients
#7
Ming-Yu Wang, Xian-Bin Wang, Xue-Hui Sun, Feng-Li Liu, Sheng-Chuan Huang
We studied the diagnostic value of high-frequency color Doppler ultrasonography (HCDU) examination in combination with anti-cyclic citrullinated peptide (anti-CCP) antibody testing in rheumatoid arthritis (RA) patients with finger joint damage. From January 2015 to December 2015, 80 patients diagnosed with RA with finger joints damage were enrolled in this study. Patients were examined with HCDU. Serum anti-CCP antibody level was tested using ELISA, and results were compared with the healthy control group. Results obtained by ELISA demonstrated that the positive rate of anti-CCP antibodies was 73...
March 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28445593/nr5a2-discovering-compounds-that-block-tumor-growth-in-pdac
#8
REVIEW
Robert Fletterick
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
April 26, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28430130/timp1-promotes-cell-survival-by-activating-the-pdk1-signaling-pathway-in-melanoma
#9
Mariana Toricelli, Fabiana H M Melo, Aline Hunger, Daniela Zanatta, Bryan E Strauss, Miriam G Jasiulionis
High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics...
April 21, 2017: Cancers
https://www.readbyqxmd.com/read/28402921/mir-155-promotes-cell-proliferation-and-inhibits-apoptosis-by-pten-signaling-pathway-in-the-psoriasis
#10
Longjiang Xu, Hong Leng, Xin Shi, Jiang Ji, Jinxiang Fu, Hong Leng
MicroRNAs (miRNAs) have been demonstrated to contribute to malignant progression in psoriasis development. The purposes of the study was to evaluated the effects of miRNA-155 on cell proliferation, migration and apoptosis in psoriasis development via PTEN singaling pathway and identify its direct target protein. Quantitative real-time RT-PCR (qRT-PCR) was performed to examine the level of miR-155 in psoriasis cells, miR-155 was downregulated in a psoriasis cell line Hacat by transfected with small interfering RNA (siRNA), respectively...
June 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28371201/ketone-bodies-mimic-the-life-span-extending-properties-of-caloric-restriction
#11
REVIEW
Richard L Veech, Patrick C Bradshaw, Kieran Clarke, William Curtis, Robert Pawlosky, M Todd King
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway...
April 3, 2017: IUBMB Life
https://www.readbyqxmd.com/read/28365441/the-multi-site-docking-protein-gab1-is-constitutively-phosphorylated-independent-from-its-recruitment-to-the-plasma-membrane-in-jak2-v617f-positive-cells-and-mediates-proliferation-of-human-erythroleukaemia-cells
#12
Hannes Bongartz, Wiebke Hessenkemper, Christian Müller, Melissa Fensky, Johannes Fritsch, Katharina Mandel, Iris Behrmann, Claude Haan, Thomas Fischer, Stephan M Feller, Fred Schaper
The constitutively active Janus kinase 2 mutant Jak2-V617F is responsible for cytokine-independent growth of hematopoietic cells and the development of myeloproliferative neoplasms, such as polycythaemia vera and essential thrombocythaemia. Cells expressing Jak2-V617F exhibit constitutive STAT, MAPK, and PI3K signalling, and constitutive association of the multi-site docking protein Gab1 to PIP3 at the plasma membrane. Here, we demonstrate the crucial role of Gab1 for the proliferation of Jak2-V617F-positive human erythroleukaemia (HEL) cells...
March 30, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28360038/insulin-receptor-and-gpcr-crosstalk-stimulates-yap-via-pi3k-and-pkd-in-pancreatic-cancer-cells
#13
Fang Hao, Qinhong Xu, Yinglan Zhao, Jan V Stevens, Steven H Young, James Sinnett-Smith, Enrique Rozengurt
We examined the impact of crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling pathways on the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in the context of human pancreatic ductal adenocarcinoma (PDAC). Stimulation of PANC-1 or MiaPaCa-2 cells with insulin and neurotensin, a potent mitogenic combination of agonists for these cells, promoted striking YAP nuclear localization and decreased YAP phosphorylation at Ser(127) and Ser(397) Challenging PDAC cells with either insulin or neurotensin alone modestly induced the expression of YAP/TEAD-regulated genes, including connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), and CXCL5, whereas the combination of neurotensin and insulin induced a marked increase in the level of expression of these genes...
March 30, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28348208/myo6-is-targeted-by-salmonella-virulence-effectors-to-trigger-pi3-kinase-signaling-and-pathogen-invasion-into-host-cells
#14
Andrew B E Brooks, Daniel Humphreys, Vikash Singh, Anthony C Davidson, Susan D Arden, Folma Buss, Vassilis Koronakis
To establish infections, Salmonella injects virulence effectors that hijack the host actin cytoskeleton and phosphoinositide signaling to drive pathogen invasion. How effectors reprogram the cytoskeleton network remains unclear. By reconstituting the activities of the Salmonella effector SopE, we recapitulated Rho GTPase-driven actin polymerization at model phospholipid membrane bilayers in cell-free extracts and identified the network of Rho-recruited cytoskeleton proteins. Knockdown of network components revealed a key role for myosin VI (MYO6) in Salmonella invasion...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28343126/pi3k-signaling-in-cancer-beyond-akt
#15
REVIEW
Evan C Lien, Christian C Dibble, Alex Toker
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K...
April 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28295876/a-vicious-partnership-between-akt-and-phlda3-to-facilitate-neuroendocrine-tumors
#16
REVIEW
Masahiro Takikawa, Rieko Ohki
Pancreatic neuroendocrine tumors (PanNET) are rare cancers that generally have a poor prognosis. Accurate diagnosis and proper treatment of these tumors requires a better understanding of the molecular mechanisms underlying the development of PanNET. It has been shown that the mTOR inhibitor everolimus can improve the progression-free survival of PanNET patients, suggesting that inhibition of the PI3K-Akt-mTOR pathway may suppress the progression of PanNET. PHLDA3 is a novel tumor suppressor protein that inhibits Akt activation by competition for binding to PIP3 ...
June 2017: Cancer Science
https://www.readbyqxmd.com/read/28292823/correction-annular-pip3-accumulation-controls-actin-architecture-and-modulates-cytotoxicity-at-the-immunological-synapse
#17
Audrey Le Floc'h, Yoshihiko Tanaka, Niels S Bantilan, Guillaume Voisinne, Grégoire Altan-Bonnet, Yoshinori Fukui, Morgan Huse
No abstract text is available yet for this article.
April 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28287114/regulation-of-inflammation-and-tumorigenesis-by-the-tipe-family-of-phospholipid-transfer-proteins
#18
REVIEW
Jason R Goldsmith, Youhai H Chen
The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation...
June 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28263967/characterization-of-pten-mutations-in-brain-cancer-reveals-that-pten-mono-ubiquitination-promotes-protein-stability-and-nuclear-localization
#19
Jr-M Yang, P Schiapparelli, H-N Nguyen, A Igarashi, Q Zhang, S Abbadi, L M Amzel, H Sesaki, A Quiñones-Hinojosa, M Iijima
PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28250113/cxcl12-induced-macropinocytosis-modulates-two-distinct-pathways-to-activate-mtorc1-in-macrophages
#20
Regina Pacitto, Isabella Gaeta, Joel A Swanson, Sei Yoshida
Although growth factors and chemokines elicit different overall effects on cells-growth and chemotaxis, respectively-and activate distinct classes of cell-surface receptors, nonetheless, they trigger similar cellular activities and signaling pathways. The growth factor M-CSF and the chemokine CXCL12 both stimulate the endocytic process of macropinocytosis, and both activate the mechanistic target of rapamycin complex 1 (mTORC1), a protein complex that regulates cell metabolism. Recent studies of signaling by M-CSF in macrophages identified a role for macropinocytosis in the activation of mTORC1, in which delivery of extracellular amino acids into lysosomes via macropinocytosis was required for activation of mTORC1...
March 2017: Journal of Leukocyte Biology
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