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Ana Raquel Ramos, William's Elong Edimo, Christophe Erneux
Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes...
September 5, 2017: Advances in Biological Regulation
S E Conduit, V Ramaswamy, M Remke, D N Watkins, B J Wainwright, M D Taylor, C A Mitchell, J M Dyson
Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3...
June 26, 2017: Oncogene
Kollu N Rao, Wei Zhang, Linjing Li, Manisha Anand, Hemant Khanna
No abstract text is available yet for this article.
October 15, 2016: Human Molecular Genetics
Elizabeth A Sierra Potchanant, Donna Cerabona, Zahi Abdul Sater, Ying He, Zejin Sun, Jeff Gehlhausen, Grzegorz Nalepa
The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity...
March 15, 2017: Molecular and Cellular Biology
Jennifer M Dyson, Sarah E Conduit, Sandra J Feeney, Sandra Hakim, Tia DiTommaso, Alex J Fulcher, Absorn Sriratana, Georg Ramm, Kristy A Horan, Rajendra Gurung, Carol Wicking, Ian Smyth, Christina A Mitchell
Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e(-/-) embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e(-/-) ciliopathy phenotypes and "normalizes" Hedgehog signaling...
January 2, 2017: Journal of Cell Biology
Shohei Nozaki, Yohei Katoh, Masaya Terada, Saki Michisaka, Teruki Funabashi, Senye Takahashi, Kenji Kontani, Kazuhisa Nakayama
ARL13B (a small GTPase) and INPP5E (a phosphoinositide 5-phosphatase) are ciliary proteins encoded by causative genes of Joubert syndrome. We here showed, by taking advantage of a visible immunoprecipitation assay, that ARL13B interacts with the IFT46 -: IFT56 (IFT56 is also known as TTC26) dimer of the intraflagellar transport (IFT)-B complex, which mediates anterograde ciliary protein trafficking. However, the ciliary localization of ARL13B was found to be independent of its interaction with IFT-B, but dependent on the ciliary-targeting sequence RVEP in its C-terminal region...
February 1, 2017: Journal of Cell Science
Shuhei Nakamura, Junya Hasegawa, Tamotsu Yoshimori
Macroautophagy (autophagy) is a multistep intracellular degradation system. Autophagosomes form, mature, and ultimately fuse with lysosomes, where their sequestered cargo molecules are digested. In contrast to autophagosome formation, our knowledge of autophagosome-lysosome fusion is limited. In a recent study, we identified a novel regulator of autophagy, INPP5E (inositol polyphosphate-5-phosphatase E), which is essential for autophagosome-lysosome fusion. INPP5E primarily functions in neuronal cells, and knockdown of the corresponding gene causes accumulation of autophagosomes by impairing fusion with lysosomes...
December 2016: Autophagy
Kollu N Rao, Wei Zhang, Linjing Li, Manisha Anand, Hemant Khanna
Ciliary trafficking defects underlie the pathogenesis of severe human ciliopathies, including Joubert Syndrome (JBTS), Bardet-Biedl Syndrome, and some forms of retinitis pigmentosa (RP). Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are common causes of RP-associated photoreceptor degeneration worldwide. While previous work has suggested that the localization of RPGR to cilia is critical to its functions, the mechanism by which RPGR and its associated cargo are trafficked to the cilia is unclear...
August 22, 2016: Human Molecular Genetics
Andrea Aguilar
No abstract text is available yet for this article.
September 2016: Nature Reviews. Nephrology
Wenyan Xu, Miaomiao Jin, Ruikun Hu, Hong Wang, Fan Zhang, Shiaulou Yuan, Ying Cao
Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PtdIns), are tightly regulated both temporally and spatially by PtdIns phosphatases and kinases. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause Joubert syndrome, a human disorder associated with numerous ciliopathic defects, including renal cyst formation, linking phosphoinositides to ciliopathies. However, the molecular mechanism by which INPP5E-mediated PtdIns signaling regulates ciliogenesis and cystogenesis is unclear...
January 2017: Journal of the American Society of Nephrology: JASN
Junya Hasegawa, Ryo Iwamoto, Takanobu Otomo, Akiko Nezu, Maho Hamasaki, Tamotsu Yoshimori
Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy...
September 1, 2016: EMBO Journal
Satria P Sajuthi, Neeraj K Sharma, Jeff W Chou, Nicholette D Palmer, David R McWilliams, John Beal, Mary E Comeau, Lijun Ma, Jorge Calles-Escandon, Jamehl Demons, Samantha Rogers, Kristina Cherry, Lata Menon, Ethel Kouba, Donna Davis, Marcie Burris, Sara J Byerly, Maggie C Y Ng, Nisa M Maruthur, Sanjay R Patel, Lawrence F Bielak, Leslie A Lange, Xiuqing Guo, Michèle M Sale, Kei Hang K Chan, Keri L Monda, Gary K Chen, Kira Taylor, Cameron Palmer, Todd L Edwards, Kari E North, Christopher A Haiman, Donald W Bowden, Barry I Freedman, Carl D Langefeld, Swapan K Das
Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits...
August 2016: Human Genetics
Eyad Kalawy Fansa, Stefanie Kristine Kösling, Eldar Zent, Alfred Wittinghofer, Shehab Ismail
The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5'-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2...
April 11, 2016: Nature Communications
Sandra Hakim, Jennifer M Dyson, Sandra J Feeney, Elizabeth M Davies, Absorn Sriratana, Monica N Koenig, Olga V Plotnikova, Ian M Smyth, Sharon D Ricardo, Robin M Hobbs, Christina A Mitchell
Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3and is mutated in ciliopathy syndromes. GermlineInpp5edeletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development uponInpp5eloss remain unknown. Here, we show conditional inactivation ofInpp5ein mouse kidney epithelium results in severe PKD and renal failure, associated with a partial reduction in cilia number and hyperactivation of PI3K/Akt and downstream mTORC1 signaling...
April 7, 2016: Human Molecular Genetics
Sarah Kittel-Schneider, Carina Lorenz, Joyce Auer, Lena Weißflog, Andreas Reif
BACKGROUND: DGKH is a replicated risk gene of bipolar disorder (BD). However, the pathophysiological role of the coded protein, diacylglycerol kinase eta, remains elusive. METHODS: In this proof-of-concept study we isolated mRNA from peripheral blood and fibroblasts of heterozygote DGKH risk variants carriers (risk haplotype rs994856/rs9525580/rs9525584 GAT) with bipolar disorder and non-risk variant carriers with and without bipolar disorder. Gene expression of DGKH1, DGKH2, INPP5E, PI4K2B, PIK4CA, PLCG2, PRKCA, PRKCD, PRKCE and PRKCH was analysed by qRT PCR...
July 1, 2016: Journal of Affective Disorders
Qingwen Xu, Yuxia Zhang, Qing Wei, Yan Huang, Jinghua Hu, Kun Ling
Defective primary cilia are causative to a wide spectrum of human genetic disorders, termed ciliopathies. Although the regulation of ciliogenesis is intensively studied, how it is initiated remains unclear. Here we show that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) and inositol polyphosphate-5-phosphatase E (INPP5E), a Joubert syndrome protein, localize to the centrosome and coordinate the initiation of ciliogenesis. PIPKIγ counteracts INPP5E in regulating tau-tubulin kinase-2 (TTBK2) recruitment to the basal body, which promotes the removal of microtubule capping protein CP110 and the subsequent axoneme elongation...
February 26, 2016: Nature Communications
Matthew J Eramo, Christina A Mitchell
The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5)P3 to yield PtdIns(3,4)P2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5)P3 despite increasing cellular levels of PtdIns(3,4)P2...
February 2016: Biochemical Society Transactions
Christin Hanke-Gogokhia, Zhijian Wu, Cecilia D Gerstner, Jeanne M Frederick, Houbin Zhang, Wolfgang Baehr
Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion ofArl3in mice causes multiorgan ciliopathy reminiscent of Bardet-Biedl or Joubert syndromes. As photoreceptors are elegantly compartmentalized and have cilia, we probed the function of ARL3 (ADP-ribosylation factor (Arf)-like 3 protein) by generating rod photoreceptor-specific (prefix(rod)) and retina-specific (prefix(ret))Arl3deletions. In predegenerate(rod)Arl3(-/-)mice, lipidated phototransduction proteins showed trafficking deficiencies, consistent with the role of ARL3 as a cargo displacement factor for lipid-binding proteins...
March 25, 2016: Journal of Biological Chemistry
Jina Park, Nayoung Lee, Adriana Kavoussi, Jeong Taeg Seo, Chul Hoon Kim, Seok Jun Moon
Cilia are highly specialized antennae-like cellular organelles. Inositol polyphosphate 5-phosphatase E (INPP5E) converts PI(4,5)P2 into PI4P and is required for proper ciliary function. Although Inpp5e mutations are associated with ciliopathies in humans and mice, the precise molecular role INPP5E plays in cilia remains unclear. Here, we report that Drosophila INPP5E (dINPP5E) regulates ciliary protein trafficking by controlling the phosphoinositide composition of ciliary membranes. Mutations in dInpp5e lead to hearing deficits due to the mislocalization of dTULP and mechanotransduction channels, Inactive and NOMPC, in chordotonal cilia...
December 29, 2015: Cell Reports
Gisela G Slaats, Christine R Isabella, Hester Y Kroes, Jennifer C Dempsey, Hendrik Gremmels, Glen R Monroe, Ian G Phelps, Karen J Duran, Jonathan Adkins, Sairam A Kumar, Dana M Knutzen, Nine V Knoers, Nancy J Mendelsohn, David Neubauer, Sotiria D Mastroyianni, Julie Vogt, Lisa Worgan, Natalya Karp, Sarah Bowdin, Ian A Glass, Melissa A Parisi, Edgar A Otto, Colin A Johnson, Friedhelm Hildebrandt, Gijs van Haaften, Rachel H Giles, Dan Doherty
BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS...
January 2016: Journal of Medical Genetics
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