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Inositol polyphosphate multikinase

Giulia Ramazzotti, Anna Maria Billi, Lucia Manzoli, Cristina Mazzetti, Alessandra Ruggeri, Christophe Erneux, Seyun Kim, Pann-Ghill Suh, Lucio Cocco, Irene Faenza
In previous studies, we have reported that phospholipase C (PLC)-β1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers. Moreover, we demonstrate that IPMK activates the same cyclin D3 promoter region targeted by PLC-β1 and that IPMK-induced promoter activation relies upon c-jun binding to the promoter, as we have shown previously for PLC-β1...
August 23, 2016: Oncotarget
Igor Cestari, Paige Haas, Nilmar Silvio Moretti, Sergio Schenkman, Ken Stuart
Kinetoplastids cause Chagas disease, human African trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection...
May 19, 2016: Cell Chemical Biology
M Merced Malabanan, Raymond D Blind
Inositol polyphosphate multikinase (IPMK, ipk2, Arg(82), ArgRIII) is an inositide kinase with unusually flexible substrate specificity and the capacity to partake in many functional protein-protein interactions (PPIs). By merging these two activities, IPMK is able to execute gene regulatory functions that are very unique and only now beginning to be recognized. In this short review, we present a brief history of IPMK, describe the structural biology of the enzyme and highlight a few recent discoveries that have shed more light on the role IPMK plays in inositide metabolism, nuclear signalling and transcriptional regulation...
February 2016: Biochemical Society Transactions
Eunha Kim, Jiyoon Beon, Seulgi Lee, Jina Park, Seyun Kim
Inositol-derived metabolites (e.g., phosphoinositides and inositol polyphosphates) are key second messengers that are essential for controlling a wide range of cellular events. Inositol polyphosphate multikinase (IPMK) exhibits complex catalytic activities that eventually yield water-soluble inositol polyphosphates (e.g., IP4 and IP5) and lipid-bound phosphatidylinositol 3,4,5-trisphosphate. A series of recent studies have suggested that IPMK may be a multifunctional regulator in the nucleus of mammalian cells...
May 2016: Advances in Biological Regulation
Ishrat Ahmed, Juan I Sbodio, Maged M Harraz, Richa Tyagi, Jonathan C Grima, Lauren K Albacarys, Maimon E Hubbi, Risheng Xu, Seyun Kim, Bindu D Paul, Solomon H Snyder
Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease...
August 4, 2015: Proceedings of the National Academy of Sciences of the United States of America
Yoshitatsu Sei, Xilin Zhao, Joanne Forbes, Silke Szymczak, Qing Li, Apurva Trivedi, Mark Voellinger, Grishma Joy, Jianying Feng, Millie Whatley, MaryPat Sussex Jones, Ursula L Harper, Stephen J Marx, Aradhana M Venkatesan, Settara C Chandrasekharappa, Mark Raffeld, Martha M Quezado, Adeline Louie, Clara C Chen, Ramona M Lim, Richa Agarwala, Alejandro A Schäffer, Marybeth S Hughes, Joan E Bailey-Wilson, Stephen A Wank
BACKGROUND & AIMS: Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer...
July 2015: Gastroenterology
Aleksey Porollo, Thomas M Sesterhenn, Margaret S Collins, Jeffrey A Welge, Melanie T Cushion
UNLABELLED: In the context of deciphering the metabolic strategies of the obligate pathogenic fungi in the genus Pneumocystis, the genomes of three species (P. carinii, P. murina, and P. jirovecii) were compared among themselves and with the free-living, phylogenetically related fission yeast (Schizosaccharomyces pombe). The underrepresentation of amino acid metabolism pathways compared to those in S. pombe, as well as the incomplete steroid biosynthesis pathway, were confirmed for P...
2014: MBio
Sookhee Bang, Yong Chen, Rexford S Ahima, Sangwon F Kim
Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosphate multikinase (IPMK) plays an important role in cellular energy metabolism and glucose-mediated AMPK regulation...
July 2014: Molecular Endocrinology
Bernadett Kolozsvari, Federica Parisi, Adolfo Saiardi
The polymer inorganic polyP (polyphosphate) and inositol phosphates, such as IP6 (inositol hexakisphosphate; also known as phytic acid), share many biophysical features. These similarities must be attributed to the phosphate groups present in these molecules. Given the ability of polyP to modify the excitation-emission spectra of DAPI we decided to investigate whether inositol phosphates possess the same property. We discovered that DAPI-IP6 complexes emit at approximately 550 nm when excited with light of wavelength 410-420 nm...
June 15, 2014: Biochemical Journal
Eunha Kim, Richa Tyagi, Joo-Young Lee, Jina Park, Young-Ran Kim, Jiyoon Beon, Po Yu Chen, Jiyoung Y Cha, Solomon H Snyder, Seyun Kim
Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes...
December 3, 2013: Proceedings of the National Academy of Sciences of the United States of America
Vihandha O Wickramasinghe, Jane M Savill, Sreenivas Chavali, Asta B Jonsdottir, Eeson Rajendra, Tamara Grüner, Ronald A Laskey, M Madan Babu, Ashok R Venkitaraman
Messenger RNA (mRNA) export from the nucleus is essential for eukaryotic gene expression. Here we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export...
September 26, 2013: Molecular Cell
Risheng Xu, Bindu D Paul, Dani R Smith, Richa Tyagi, Feng Rao, A Basit Khan, Daniel J Blech, M Scott Vandiver, Maged M Harraz, Prasun Guha, Ishrat Ahmed, Nilkantha Sen, Michela Gallagher, Solomon H Snyder
Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters...
October 1, 2013: Proceedings of the National Academy of Sciences of the United States of America
Risheng Xu, Solomon H Snyder
No abstract text is available yet for this article.
June 15, 2013: Cell Cycle
Risheng Xu, Nilkantha Sen, Bindu D Paul, Adele M Snowman, Feng Rao, M Scott Vandiver, Jing Xu, Solomon H Snyder
The tumor suppressor protein p53 is a critical stress response transcription factor that induces the expression of genes leading to cell cycle arrest, apoptosis, and tumor suppression. We found that mammalian inositol polyphosphate multikinase (IPMK) stimulated p53-mediated transcription by binding to p53 and enhancing its acetylation by the acetyltransferase p300 independently of its inositol phosphate and lipid kinase activities. Genetic or RNA interference (RNAi)-mediated knockdown of IPMK resulted in decreased activation of p53, decreased recruitment of p53 and p300 to target gene promoters, abrogated transcription of p53 target genes, and enhanced cell viability...
April 2, 2013: Science Signaling
Corinne Niger, Maria A Luciotti, Atum M Buo, Carla Hebert, Vy Ma, Joseph P Stains
Connexin43 (Cx43) plays a critical role in osteoblast function and bone mass accrual, yet the identity of the second messengers communicated by Cx43 gap junctions, the targets of these second messengers and how they regulate osteoblast function remain largely unknown. We have shown that alterations of Cx43 expression in osteoblasts can impact the responsiveness to fibroblast growth factor-2 (FGF2), by modulating the transcriptional activity of runt-related transcription factor 2 (Runx2). In this study, we examined the contribution of the phospholipase Cγ1/inositol polyphosphate/protein kinase C delta (PKCδ) cascade to the Cx43-dependent transcriptional response of MC3T3 osteoblasts to FGF2...
June 2013: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Joo-Young Lee, Young-ran Kim, Jina Park, Seyun Kim
Inositol phosphates (IPs) act as signaling messengers to regulate various cellular processes such as growth. Inositol polyphosphate multikinase (IPMK) generates inositol tetrakis- and pentakisphosphates (IP₄ and IP₅), acting as a key enzyme for inositol polyphosphate biosynthesis. IPMK was initially discovered as an essential subunit of the arginine-sensing transcription complex in budding yeast. In mammals, IPMK is also known as a physiologically important phosphatidylinositol 3 kinase (PI3K) that forms phosphatidylinositol 3,4,5-trisphosphate (PIP₃), which activates Akt/PKB and stimulates its signaling...
October 2012: Annals of the New York Academy of Sciences
Daniel Bosch, Adolfo Saiardi
Inositol phosphates are key signaling molecules affecting a large variety of cellular processes. Inositol-polyphosphate multikinase (IPMK) is a central component of the inositol phosphate biosynthetic routes, playing essential roles during development. IPMK phosphorylates inositol 1,4,5-trisphosphate to inositol tetrakisphosphate and subsequently to inositol pentakisphosphate and has also been described to function as a lipid kinase. Recently, a catalytically inactive mammalian IPMK was reported to be involved in nutrient signaling by way of mammalian target of rapamycin and AMP-activated protein kinase...
November 2, 2012: Journal of Biological Chemistry
Ying Wang, Hsien-yu Wang
Wnt3a binds Frizzled-1 and the LRP5/6 co-receptors, ultimately activating Lef/Tcf-sensitive gene transcription in development. Inositol polyphosphate multikinase, IPMK, which possesses inositol phosphate kinase and lipid inositol kinase activities, is essential in Wnt3a regulation of its canonical pathway as well as physiologically in AMPK signaling. In the current report we show that translocation of IPMK to the cell membrane, where its substrates exist in high abundance, is obligate to its function in Wnt signaling...
December 2012: Cellular Signalling
Robert Taylor, Po-Hao Chen, Chia-Ching Chou, Jasmin Patel, Shengkan V Jin
Inositol phosphates are implicated in the regulation of autophagy; however, the exact role of each inositol phosphate species is unclear. In this study, we systematically analyzed the highly conserved inositol polyphosphate synthesis pathway in S. cerevisiae for its role in regulating autophagy. Using yeast mutants that harbored a deletion in each of the genes within the inositol polyphosphate synthesis pathway, we found that deletion of KCS1, and to a lesser degree IPK2, led to a defect in autophagy. KCS1 encodes an inositol hexakisphosphate/heptakisposphate kinase that synthesizes 5-IP(7) and IP(8); and IPK2 encodes an inositol polyphosphate multikinase required for synthesis of IP(4) and IP(5)...
September 2012: Autophagy
Raymond D Blind, Miyuki Suzawa, Holly A Ingraham
Phosphatidylinositol 4,5-bisphosphate (PIP₂) is best known as a plasma membrane-bound regulatory lipid. Although PIP₂ and phosphoinositide-modifying enzymes coexist in the nucleus, their nuclear roles remain unclear. We showed that inositol polyphosphate multikinase (IPMK), which functions both as an inositol kinase and as a phosphoinositide 3-kinase (PI3K), interacts with the nuclear receptor steroidogenic factor 1 (SF-1) and phosphorylates its bound ligand, PIP₂. In vitro studies showed that PIP₂ was not phosphorylated by IPMK if PIP₂ was displaced or blocked from binding to the large hydrophobic pocket of SF-1 and that the ability to phosphorylate PIP₂ bound to SF-1 was specific to IPMK and did not occur with type 1 p110 PI3Ks...
June 19, 2012: Science Signaling
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