Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities

Inositol phosphate kinase 2 (Ipk2), also known as IP multikinase IPMK, is an evolutionarily conserved protein that initiates production of inositol phosphate intracellular messengers (IPs), which are critical for regulating nuclear and cytoplasmic processes. Here we report that Ipk2 kinase activity is required for the development of the adult fruit fly epidermis. Ipk2 mutants show impaired development of their imaginal discs, the primordial tissues that form the adult epidermis. Although disk tissue seems to specify normally during early embryogenesis, loss of Ipk2 activity results in increased apoptosis and impairment of proliferation during larval and pupal development. The proliferation defect is in part attributed to a reduction in JAK/STAT signaling, possibly by controlling production or secretion of the pathway’s activating ligand, Unpaired. Constitutive activation of the JAK/STAT pathway downstream of Unpaired partially rescues the disk growth defects in Ipk2 mutants. Thus, IP production is essential for proliferation of the imaginal discs, in part, by regulating JAK/STAT signaling. Our work demonstrates an essential role for Ipk2 in producing inositide messengers required for imaginal disk tissue maturation and subsequent formation of adult body structures and provides molecular insights to signaling pathways involved in tissue growth and stability during development.

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A novel Entamoeba histolytica inositol phosphate kinase catalyzes the formation of 5PP-Ins(1,2,3,4,6)P5

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2011.09.008 ◽

2012 ◽

Vol 181 (1) ◽

pp. 49-52 ◽

Cited By ~ 5

Author(s):

Benjamin Löser ◽

Marcus M. Nalaskowski ◽

Werner Fanick ◽

Hongying Lin ◽

Egbert Tannich ◽

...

Keyword(s):

Entamoeba Histolytica ◽

Inositol Phosphate ◽

Inositol Phosphate Kinase

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Integration of Inositol Phosphate Signaling Pathways via Human ITPK1

Journal of Biological Chemistry ◽

10.1074/jbc.m703121200 ◽

2007 ◽

Vol 282 (38) ◽

pp. 28117-28125 ◽

Cited By ~ 33

Author(s):

Philip P. Chamberlain ◽

Xun Qian ◽

Amanda R. Stiles ◽

Jaiesoon Cho ◽

David H. Jones ◽

...

Keyword(s):

Plasma Membrane ◽

Chloride Channels ◽

Inositol Phosphates ◽

Inositol Phosphate ◽

Structural Features ◽

Signaling Mechanism ◽

Metabolic Role ◽

Inositol 1,4,5 Trisphosphate ◽

High Resolution Structure ◽

Substrate Regulation

Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role.

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Characterization of a multifunctional inositol phosphate kinase from rice and barley belonging to the ATP-grasp superfamily

Gene ◽

10.1016/j.gene.2007.04.018 ◽

2007 ◽

Vol 397 (1-2) ◽

pp. 114-125 ◽

Cited By ~ 34

Author(s):

Lone Josefsen ◽

Lisbeth Bohn ◽

Mikael Blom Sørensen ◽

Søren K. Rasmussen

Keyword(s):

Inositol Phosphate ◽

Inositol Phosphate Kinase

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Molecular Cloning and Pharmacological Characterization of Two Novel GnRH Receptors in the Lamprey (Petromyzon marinus)

Endocrinology ◽

10.1210/en.2012-1217 ◽

2012 ◽

Vol 153 (7) ◽

pp. 3345-3356 ◽

Cited By ~ 13

Author(s):

Nerine T. Joseph ◽

Allisan Aquilina-Beck ◽

Caryn MacDonald ◽

Wayne A. Decatur ◽

Jeffrey A. Hall ◽

...

Keyword(s):

Binding Affinity ◽

Intracellular Signaling ◽

Inositol Phosphate ◽

Sea Lamprey ◽

Structural Features ◽

Receptor Subtypes ◽

Pharmacological Characterization ◽

Functional Studies ◽

Gnrh Receptors ◽

Precursor Transcript

This paper reports the identification, expression, binding kinetics, and functional studies of two novel type III lamprey GnRH receptors (lGnRH-R-2 and lGnRH-R-3) in the sea lamprey, a basal vertebrate. These novel GnRH receptors share the structural features and amino acid motifs common to other known gnathostome GnRH receptors. The ligand specificity and activation of intracellular signaling studies showed ligands lGnRH-II and -III induced an inositol phosphate (IP) response at lGnRH-R-2 and lGnRH-R-3, whereas the ligand lGnRH-I did not stimulate an IP response. lGnRH-II was a more potent activator of lGnRH-R-3 than lGnRH-III. Stimulation of lGnRH-R-2 and lGnRH-R-3 testing all three lGnRH ligands did not elicit a cAMP response. lGnRH-R-2 has a higher binding affinity in response to lGnRH-III than lGnRH-II, whereas lGnRH-R-3 has a higher binding affinity in response to lGnRH-II than IGnRH-III. lGnRH-R-2 precursor transcript was detected in a wide variety of tissues including the pituitary whereas lGnRH-R-3 precursor transcript was not as widely expressed and primarily expressed in the brain and eye of male and female lampreys. From our phylogenetic analysis, we propose that lGnRH-R-1 evolved from a common ancestor of all vertebrate GnRH receptors and lGnRH-R-2 and lGnRH-R-3 likely occurred due to a gene duplication within the lamprey lineage. In summary, we propose from our findings of receptor subtypes in the sea lamprey that the evolutionary recruitment of specific pituitary GnRH receptor subtypes for particular physiological functions seen in later evolved vertebrates was an ancestral character that first arose in a basal vertebrate.

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