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IQGAP1 makes PI(3)K signalling as easy as PIP, PIP, PIP.
Rameh LE, Mackey AM
(2016) Nat Cell Biol 18: 1263-1265
MeSH Terms: Animals, Humans, Models, Biological, Neoplasms, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, Signal Transduction, ras GTPase-Activating Proteins
Show Abstract · Added November 26, 2018
Despite being one of the most studied signalling pathways, precisely how phospholipid synthesis is regulated in the phosphoinositide signalling cascade remains unclear. The scaffold protein IQGAP1 is now shown to orchestrate the assembly of a multi-enzyme complex that streamlines PtdIns(3,4,5)P synthesis to facilitate Akt activation in response to extracellular stimuli.
0 Communities
1 Members
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MeSH Terms
Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.
Van Driest SL, McGregor TL, Velez Edwards DR, Saville BR, Kitchner TE, Hebbring SJ, Brilliant M, Jouni H, Kullo IJ, Creech CB, Kannankeril PJ, Vear SI, Brothers KB, Bowton EA, Shaffer CM, Patel N, Delaney JT, Bradford Y, Wilson S, Olson LM, Crawford DC, Potts AL, Ho RH, Roden DM, Denny JC
(2015) PLoS One 10: e0127791
MeSH Terms: Adult, Aged, Chromosomes, Human, Chromosomes, Human, Pair 6, Connexin 43, Creatinine, Female, GTPase-Activating Proteins, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Vancomycin
Show Abstract · Added February 22, 2016
Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
0 Communities
5 Members
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15 MeSH Terms
Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.
GTEx Consortium
(2015) Science 348: 648-60
MeSH Terms: Alleles, Blood Pressure, Disease, GTPase-Activating Proteins, Gene Expression Regulation, Gene Regulatory Networks, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Multigene Family, Organ Specificity, Pilot Projects, Quantitative Trait Loci, RNA Splicing, RNA, Untranslated, Sequence Analysis, RNA, Tibial Arteries, Transcriptome
Show Abstract · Added April 13, 2017
Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.
Copyright © 2015, American Association for the Advancement of Science.
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20 MeSH Terms
Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner.
Kjøbsted R, Treebak JT, Fentz J, Lantier L, Viollet B, Birk JB, Schjerling P, Björnholm M, Zierath JR, Wojtaszewski JF
(2015) Diabetes 64: 2042-55
MeSH Terms: AMP-Activated Protein Kinases, Aminoimidazole Carboxamide, Animals, Biological Transport, Blotting, Western, Electrophoresis, Polyacrylamide Gel, GTPase-Activating Proteins, Insulin, Mice, Muscle, Skeletal, Phosphorylation, Ribonucleotides
Show Abstract · Added May 16, 2019
An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr(649) and Ser(711) in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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MeSH Terms
Phosphatidylserine flipping enhances membrane curvature and negative charge required for vesicular transport.
Xu P, Baldridge RD, Chi RJ, Burd CG, Graham TR
(2013) J Cell Biol 202: 875-86
MeSH Terms: ATP-Binding Cassette Transporters, Adenosine Triphosphatases, Amino Acid Motifs, Amino Acid Sequence, Blotting, Western, Calcium-Transporting ATPases, Cell Membrane, DNA-Binding Proteins, Endosomes, GTPase-Activating Proteins, Immunoprecipitation, Membrane Lipids, Models, Molecular, Molecular Sequence Data, Phosphatidylserines, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Transport Vesicles, trans-Golgi Network
Show Abstract · Added May 29, 2014
Vesicle-mediated protein transport between organelles of the secretory and endocytic pathways is strongly influenced by the composition and organization of membrane lipids. In budding yeast, protein transport between the trans-Golgi network (TGN) and early endosome (EE) requires Drs2, a phospholipid translocase in the type IV P-type ATPase family. However, downstream effectors of Drs2 and specific phospholipid substrate requirements for protein transport in this pathway are unknown. Here, we show that the Arf GTPase-activating protein (ArfGAP) Gcs1 is a Drs2 effector that requires a variant of the ArfGAP lipid packing sensor (+ALPS) motif for localization to TGN/EE membranes. Drs2 increases membrane curvature and anionic phospholipid composition of the cytosolic leaflet, both of which are sensed by the +ALPS motif. Using mutant forms of Drs2 and the related protein Dnf1, which alter their ability to recognize phosphatidylserine, we show that translocation of this substrate to the cytosolic leaflet is essential for +ALPS binding and vesicular transport between the EE and the TGN.
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20 MeSH Terms
Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability.
Zebda N, Tian Y, Tian X, Gawlak G, Higginbotham K, Reynolds AB, Birukova AA, Birukov KG
(2013) J Biol Chem 288: 18290-9
MeSH Terms: Adherens Junctions, Antigens, CD, Binding Sites, Blotting, Western, Cadherins, Catenins, Cell Membrane, Cell Membrane Permeability, Cells, Cultured, Cytoskeleton, Endothelial Cells, Fluorescent Antibody Technique, GTPase-Activating Proteins, Guanine Nucleotide Exchange Factors, HEK293 Cells, Humans, Mutation, Phosphatidylcholines, Protein Binding, Protein Interaction Mapping, Repressor Proteins, Thrombin, p21-Activated Kinases, rac1 GTP-Binding Protein
Show Abstract · Added March 7, 2014
p120-catenin is a multidomain intracellular protein, which mediates a number of cellular functions, including stabilization of cell-cell transmembrane cadherin complexes as well as regulation of actin dynamics associated with barrier function, lamellipodia formation, and cell migration via modulation of the activities of small GTPAses. One mechanism involves p120 catenin interaction with Rho GTPase activating protein (p190RhoGAP), leading to p190RhoGAP recruitment to cell periphery and local inhibition of Rho activity. In this study, we have identified a stretch of 23 amino acids within the C-terminal domain of p120 catenin as the minimal sequence responsible for the recruitment of p190RhoGAP (herein referred to as CRAD; catenin-RhoGAP association domain). Expression of the p120-catenin truncated mutant lacking the CRAD in endothelial cells attenuated effects of barrier protective oxidized phospholipid, OxPAPC. This effect was accompanied by inhibition of membrane translocation of p190RhoGAP, increased Rho signaling, as well as suppressed activation of Rac1 and its cytoskeletal effectors PAK1 (p21-activated kinase 1) and cortactin. Expression of p120 catenin-truncated mutant lacking CRAD also delayed the recovery process after thrombin-induced endothelial barrier disruption. Concomitantly, RhoA activation and downstream signaling were sustained for a longer period of time, whereas Rac signaling was inhibited. These data demonstrate a critical role for p120-catenin (amino acids 820-843) domain in the p120-catenin·p190RhoGAP signaling complex assembly, membrane targeting, and stimulation of p190RhoGAP activity toward inhibition of the Rho pathway and reciprocal up-regulation of Rac signaling critical for endothelial barrier regulation.
1 Communities
1 Members
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24 MeSH Terms
IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors.
Jameson KL, Mazur PK, Zehnder AM, Zhang J, Zarnegar B, Sage J, Khavari PA
(2013) Nat Med 19: 626-630
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Tumor, DNA Mutational Analysis, Drug Resistance, Neoplasm, Humans, Indoles, MAP Kinase Signaling System, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Neoplasm Transplantation, Neoplasms, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins B-raf, Sequence Homology, Amino Acid, Sulfonamides, Vemurafenib, Wound Healing, ras GTPase-Activating Proteins, ras Proteins
Show Abstract · Added October 22, 2013
Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.
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22 MeSH Terms
AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
Wang HY, Ducommun S, Quan C, Xie B, Li M, Wasserman DH, Sakamoto K, Mackintosh C, Chen S
(2013) Biochem J 449: 479-89
MeSH Terms: Adipocytes, Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Cells, Cultured, Female, GTPase-Activating Proteins, Glucose, Glucose Tolerance Test, Glucose Transporter Type 4, Glycogen Synthase Kinase 3, Humans, Hypoglycemic Agents, In Vitro Techniques, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Knockout, Muscle, Skeletal, Phosphoenolpyruvate Carboxykinase (GTP), Phosphorylation
Show Abstract · Added July 21, 2014
AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
1 Communities
0 Members
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24 MeSH Terms
IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse".
Neel NF, Sai J, Ham AJ, Sobolik-Delmaire T, Mernaugh RL, Richmond A
(2011) PLoS One 6: e23813
MeSH Terms: Chemotaxis, Chromatography, Liquid, HEK293 Cells, HL-60 Cells, Humans, Intercellular Junctions, Interleukin-8, Mass Spectrometry, Protein Binding, Proteomics, Receptors, Interleukin-8B, cdc42 GTP-Binding Protein, ras GTPase-Activating Proteins
Show Abstract · Added June 6, 2013
BACKGROUND - Chemotaxis is essential for a number of physiological processes including leukocyte recruitment. Chemokines initiate intracellular signaling pathways necessary for chemotaxis through binding seven transmembrane G protein-couple receptors. Little is known about the proteins that interact with the intracellular domains of chemokine receptors to initiate cellular signaling upon ligand binding. CXCR2 is a major chemokine receptor expressed on several cell types, including endothelial cells and neutrophils. We hypothesize that multiple proteins interact with the intracellular domains of CXCR2 upon ligand stimulation and these interactions comprise a "chemosynapse", and play important roles in transducing CXCR2 mediated signaling processes.
METHODOLOGY/PRINCIPAL FINDINGS - In an effort to define the complex of proteins that assemble upon CXCR2 activation to relay signals from activated chemokine receptors, a proteomics approach was employed to identify proteins that co-associate with CXCR2 with or without ligand stimulation. The components of the CXCR2 "chemosynapse" are involved in processes ranging from intracellular trafficking to cytoskeletal modification. IQ motif containing GTPase activating protein 1 (IQGAP1) was among the novel proteins identified to interact directly with CXCR2. Herein, we demonstrate that CXCR2 co-localizes with IQGAP1 at the leading edge of polarized human neutrophils and CXCR2 expressing differentiated HL-60 cells. Moreover, amino acids 1-160 of IQGAP1 directly interact with the carboxyl-terminal domain of CXCR2 and stimulation with CXCL8 enhances IQGAP1 association with Cdc42.
CONCLUSIONS - Our studies indicate that IQGAP1 is a novel essential component of the CXCR2 "chemosynapse".
2 Communities
2 Members
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13 MeSH Terms
Conservation of hearing and protection of auditory hair cells against trauma-induced losses by local dexamethasone therapy: molecular and genetic mechanisms.
Van De Water TR, Abi Hachem RN, Dinh CT, Bas E, Haake SM, Hoosien G, Vivero R, Chan S, He J, Eshraghi AA, Angeli SI, Telischi FF, Balkany TJ
(2010) Cochlear Implants Int 11 Suppl 1: 42-55
MeSH Terms: Animals, Apoptosis, Auditory Threshold, Cells, Cultured, Dexamethasone, Disease Models, Animal, Down-Regulation, Electrodes, Implanted, GTPase-Activating Proteins, Gene Expression Regulation, Guinea Pigs, Hair Cells, Auditory, Hearing Loss, In Vitro Techniques, Organ of Corti, Random Allocation, Real-Time Polymerase Chain Reaction, Reference Values, Tumor Necrosis Factor-alpha, Up-Regulation, Wounds and Injuries
Show Abstract · Added April 18, 2017
HYPOTHESIS - Dexamethasone (DXM) protects hearing against trauma-induced loss.
MATERIALS - in vivo: A guinea pig model of electrode induced trauma (EIT)-induced hearing loss was used to locally deliver dexamethasone. In vitro: TNF-α-challenged organ of Corti explants treated with DXM or polymer-eluted DXM +/- PI3K/Akt/PkB/NFkB inhibitors were used for hair cells count and gene expression studies.
RESULTS - in vivo: local DXM treatment of EIT-animals prevents trauma-induced loss of ABR thresholds that occurs in EIT-animals and EIT-animals treated with the carrier solution (i.e., AP), and prevented loss of auditory hair cells. In vitro: DXM and polymer-eluted DXM were equally effective in protecting hair cells from ototoxic levels of TNF-α Inhibitor treated explants demonstrated that DXM treatment requires both Akt/PKB and NFkB signalling for otoprotection. DXM treatment of explants showed up regulation of anti-apoptosis related genes (i.e., Bcl-2, Bcl-xl) and down regulation of pro-apoptosis related genes (i.e., Bax, TNFR-1).
CONCLUSIONS - DXM exert its otoprotective action by activation of cell signal molecules (e.g., NFkB) that alter the expression of anti- and pro-apoptosis genes.
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21 MeSH Terms