The IUPHAR/BPS Guide to Pharmacology. phosphatidylinositol-5-phosphate 4-kinase type 2 beta - Phosphatidylinositol phosphate kinases. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.

Yeast and mammalian septins associate with biological membranes through a highly conserved polybasic region at the N-terminus of the GTP-binding domain (Fig. 2A). Through this region, recombinant yeast septins associate preferentially with phosphatidylinositol (4)-phosphate [PtdIns(4)P] and phosphatidylinositol (5)-phosphate [PtdIns(5)P], whereas recombinant SEPT4 specifically binds phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] and phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] (Casamayor and Snyder, 2003; Zhang et al., 1999). In yeast cells that exhibit defective PtdIns(4)P synthesis, septins fail to assemble properly at the mother-bud neck (Casamayor and Snyder, 2003). In mammalian cells, sequestration of PtdIns(4,5)P2 and reduction of its overall level at the membrane leads to the loss of SEPT4 filaments (Zhang et al., 1999), and lipid-based signaling events and PtdIns(4,5)P2-mediated regulation of the actin cytoskeleton might indirectly influence septin ...

PIP5K isoforms appear to play multiple roles in the phagocytic process. A recent study found that PIP5K-γ influences the ability of phagocytic receptors to cluster after ligand engagement (Mao et al., 2009). This step precedes and is essential for the subsequent rearrangement of actin via WASP and Arp2/3, a complex event that requires PIP5K-α. Actin undergoes an acute biphasic change during phagocytosis: it is initially polymerized at sites of particle contact and pseudopod protrusion and is then disassembled from the base of the phagocytic cup (Botelho et al., 2000). Disassembly is required for proper sealing and internalization of the target particles and also likely for fusion with endomembranes (OReilly et al., 2003; Scott et al., 2005). PI4,5P2 appears to play a key role in both phases of actin remodelling: polymerization is accompanied by an increase in the local concentration of PI4,5P2, whereas the phosphoinositide virtually disappears from the base of the phagosome as actin ...

The relationship between receptor binding of the formylated peptide chemoattractant formylmethionylleucylphenylalanine (fMet-Leu-Phe), lysosomal enzyme secretion and metabolism of membrane phospholipids was evaluated in both human polymorphonuclear leucocytes (PMN) and the dimethyl sulphoxide (Me2SO)-stimulated human myelomonocytic HL-60 leukaemic cell line. In both cell types, exposure to fMet-Leu-Phe (100 nM) induced rapid lysosomal enzyme secretion (maximal release less than 30 s) and marked changes in the 32P-labelling of the inositol lipids phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] as well as phosphatidic acid (PtdA). Specifically, levels of [32P]PtdIns and [32P]PtdIns(4,5)P2 decreased rapidly (peak decrease at 10-15s), with a subsequent increase at 30 s and later. PtdIns4P and PtdA showed only an increase. In Me2SO-differentiated HL-60 cells prelabelled with [3H]inositol for 20 h, fMet-Leu-Phe caused a ...

The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).

Downstream of tyrosine kinase (Dok) proteins Dok-1 and Dok-2 are involved in T cell homeostasis maintenance. Dok protein tyrosine phosphorylation plays a key role in establishing negative feedback loops of T cell signaling. These structurally related adapter molecules contain a pleckstrin homology (PH) domain generally acting as a lipid/protein-interacting module. We show that the presence of this PH domain is necessary for the tyrosine phosphorylation of Dok proteins and their negative functions in T cells. We find that Dok-1/Dok-2 PH domains bind in vitro to the rare phosphoinositide species, phosphatidylinositol 5-phosphate (PtdIns5P). Dok tyrosine phosphorylation correlates with PtdIns5P production in T cells upon TCR triggering. Furthermore, we demonstrate that PtdIns5P increase regulates Dok tyrosine phosphorylation in vivo. Together, our data identify a novel lipid mediator in T cell signaling and suggest that PH-PtdIns5P interactions regulate T cell responses.

Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting. ...

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene. The principal enzymatic activity of PIKfyve is to phosphorylate PtdIns3P to PtdIns(3,5)P2. PIKfyve activity is responsible for the production of both PtdIns(3,5)P2 and phosphatidylinositol 5-phosphate (PtdIns5P). PIKfyve is a large protein, containing a number of functional domains and expressed in several spliced forms. The reported full-length mouse and human cDNA clones encode proteins of 2052 and 2098 amino acid residues, respectively. By directly binding membrane PtdIns(3)P, the FYVE finger domain of PIKfyve is essential in localizing the protein to the cytosolic leaflet of endosomes. Impaired PIKfyve enzymatic activity by dominant-interfering mutants, siRNA- mediated ablation or pharmacological inhibition causes endosome enlargement and cytoplasmic vacuolation due to impaired PtdIns(3,5)P2 synthesis. Thus, via PtdIns(3,5)P2 production, PIKfyve participates in several ...

This enzyme hydrolyses 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. The enzyme also shows activity toward (PtdIns(1,3,4,5)P4) [5]. The enzyme is involved in several signal transduction pathways in the immune system leading to an adverse range of effects ...

The following pictures illustrate how the lipids must move apart to accommodate the insertion of helix zero. The first picture shows 2 different views of the ENTH domain with a space filled PtdIns(4,5)P2 docked in the structure. In the bottom picture a membrane (to scale) is added such that the PtdIns(4,5)P2 is inserted and consequently helix zero is buried. One can image a space filled helix zero an d the number of lipids that would have to be displaced to accommodate epsin docking on the membrane ...

Pleckstrin homology (PH) domains are small protein modules known for their ability to bind phosphoinositides and to drive membrane recruitment of their host proteins. We investigated phosphoinositide binding (in vitro and in vivo) and subcellular localization, and we modeled the electrostatic proper …

Order Anti-human phosphatidylinositol-3-phosphate phosphatidylinositol 5-kinase type III PAb 02012560599 at Gentaur phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, III PAb

TY - JOUR. T1 - The regulation of membrane to cytosol partitioning of signalling proteins by phosphoinositides and their soluble headgroups. AU - Downes, C Peter. AU - Gray, Alexandra. AU - Fairservice, A. AU - Safrany, S T. AU - Batty, Ian H. AU - Fleming, Ian Neil. PY - 2005/12. Y1 - 2005/12. N2 - Inositol phospholipids [PIs (phosphoinositides)] represent a group of membrane-tethered signalling molecules which differ with respect to the number and distribution of monoester phosphate groups around the inositol ring. They function by binding to proteins which possess one of several domains that bind a particular PI species, often with high affinity and specificity. PH (pleckstrin homology) domains for example possess ligand-binding pockets that are often lined with positively charged residues and which bind PIs with varying degrees of specificity. Several PH domains bind not only PIs, but also their cognate headgroups, many of which occur naturally in cells as relatively abundant cytosolic ...

Tcell anergy is one of the mechanisms thought to act in the periphery to ensure tolerance to self. The term anergy was first used to describe T cell clones rendered unresponsive to subsequent restimulation by first activating them through the TCR (signal 1) without appropriate costimulation (signal 2) (1) or, more recently, using an altered peptide ligand for activation (2). The characteristic feature of this induced unresponsiveness was the inability of the anergic T cells to proliferate or produce IL-2 following subsequent optimal restimulation (3). Anergic T cells appeared to have a defect in signaling pathways upstream of transcription of the IL-2 gene (4, 5, 6). Additional studies demonstrated the presence of cis-dominant negative regulatory elements affecting IL-2 transcription (7, 8). The recent finding of increased general receptor of phosphoinositides-1 expression indicated that broader genetic changes may accompany the induction and maintenance of the anergic phenotype (9). Our ...

In this study, we demonstrate a previously unrecognized role for PPIP5K1 in regulating cell death in response to genotoxic stress. We observed that overexpression of PPIP5K1 in HEK 293 cells protected them from apoptosis triggered by etoposide and other agents, in contrast to overexpression of another InsPP -generating enzyme, IP6K2, which sensitizes cells to cytotoxic agents [5, 6, 7, 22, 2322, 23]. After measuring the impact of PPIP5K1 on an array of apoptosis-related proteins, we also observed that PPIP5K1 alters phosphorylation of p53 at three key residues, which suggests a mechanism through which PPIP5K1 acts.. We observed the protection provided by PPIP5K1 to be dependent on the production of InsPP, as the anti-apoptotic activity provided was lost in cells expressing a kinase-impaired mutant. Previous reports have indicated that total cellular levels of InsPP are not significantly affected by over expression of PPIP5K1. We therefore cannot unambiguously conclude that it is the production ...

The regulation of the synthesis of PtdIns(4,5)P2 is emerging as being as complex as we might expect from the multi-functional nature of this lipid. In the present chapter we focus on one aspect of inositide metabolism, which is the functions of the Type II PIPkins (Type II PtdInsP kinases). These are primarily PtdIns5P 4-kinases, although in vitro they will also phosphorylate PtdIns3P to PtdIns(3,4)P2. Thus they have three, not necessarily exclusive, functions: to make PtdIns(4,5)P2 by a quantitatively minor route, to remove PtdIns5P and to make PtdIns(3,4)P2 by a route that does not involve a Class I PtdIns 3-kinase. None of these three possible functions has yet been unambiguously proven or ruled out. Of the three isoforms, α and β are widely expressed, the IIα being predominantly cytosolic and the IIβ primarily nuclear. PIPkin IIγ has a much more restricted tissue expression pattern, and appears to be localized primarily to intracellular vesicles. Here we introduce in turn each of the ...

The list of Phosphatidylcholine products offered by Avanti is designed to provide compounds having a variety of physical properties. Products available include

The phosphatidylinositol phosphate kinases (PIPkins) are a family of enzymes involved in regulating levels of several functionally important inositol phospholipids within cells. The PIPkin family is subdivided into three on the basis of substrate specificity, each subtype presumably regulating levels of different subsets of the inositol lipids. The physiological function of the type II isoforms, which exhibit a preference for phosphatidylinositol 5-phosphate, a lipid about which very little is known, is particularly poorly understood. In the present study, we demonstrate interaction between, and co-immunoprecipitation of, type IIα PIPkin with the related, but biochemically and immunologically distinct, type I PIPkin isoforms. Type IIα PIPkin interacts with all three known type I PIPkins (α, β and γ), and in each case co-expression of the type I isoform with type IIα results in recruitment of the latter from the cytosol to the plasma membrane of the cell. This change in subcellular ...

In the present work, we have investigated mechanisms involved in the nucleotide-dependent regulation of clathrin-coated pit nucleation at the synapse. Our results implicate ARF6 in this process and demonstrate two effects of the GTP-bound form of this small GTPase; stimulation of the recruitment of clathrin/AP-2 to presynaptic membranes and binding plus activation of PIPKIγ. They also suggest that the two effects are related and that PI(4,5)P2 production by PIPKIγ stimulation represents the major mechanism through which ARF6 enhances clathrin/AP-2 recruitment. The action of GTP-ARF6 on clathrin/AP-2 recruitment mimics the effect of GTPγs, and its effects are antagonized by experimental manipulations that prevent either ARF activation (i.e., dominant-negative ARF6) or PI(4,5)P2 production and availability (i.e., kinase inhibition, PIPKIγ depletion, and PI(4,5)P2 hydrolysis by synaptojanins inositol 5′-phosphatase domain). These results strongly indicate that enhanced clathrin coat ...

Resnick et al. provide new insight into the biological roles of the enzyme inositol polyphosphate multikinase (IPMK, also called Ipk2). The protein was so named because it phosphorylates multiple sites on water-soluble inositol polyphosphate rings. However, Resnick et al. show that in vitro and in vivo, IPMKs from yeast and mammals have lipid inositol kinase activity. This activity is highly specific for the D-3 position of the inositol ring--even more so than the better known phosphoinositide 3-kinases (PI3Ks), which, in mammals, generate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] in response to activated receptor tyrosine kinases. Unlike PI3K, though, IPMK was found almost exclusively in the nucleus of transfected yeast or human cells. IPMK had been previously implicated in control of gene expression in yeast, and Resnick et al. used experiments in yeast lacking phospholipase C (which consequently have no highly phosphorylated soluble inositol polyphosphates) to show that ...

Salinity is a major constraint for intrinsically salt sensitive grain legume chickpea. Chickpea exhibits large genetic variation amongst cultivars, which show better yields in saline conditions but still need to be improved further for sustainable crop production. Based on previous multi-location physiological screening, JG 11 (salt tolerant) and ICCV 2 (salt sensitive) were subjected to salt stress to evaluate their physiological and transcriptional responses. A total of ~480 million RNA-Seq reads were sequenced from root tissues which resulted in identification of 3,053 differentially expressed genes (DEGs) in response to salt stress. Reproductive stage shows high number of DEGs suggesting major transcriptional reorganization in response to salt to enable tolerance. Importantly, cationic peroxidase, Aspartic ase, NRT1/PTR, phosphatidylinositol phosphate kinase, DREB1E and ERF genes were significantly up-regulated in tolerant genotype. In addition, we identified a suite of important genes ...

The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing. In these conditions, inhibition of PTEN catalysis is being explored as a potentially beneficial therapeutic intervention. Here, an overview of human diseases and conditions in which PTEN inhibition could be beneficial is presented, together with an update on the current status of specific small molecule inhibitors of PTEN enzymatic activity, their use in experimental

Sorting nexin 27 (SNX27) controls the endosomal to cell-surface recycling of diverse transmembrane protein cargos. Critical to this function is the recruitment of SNX27 to endosomes through the binding of phosphatidylinositol-3-phosphate (PtdIns3P) by the phox-homology (PX) domain. In T cells, SNX27 is polarized to the immunological synapse (IS) in an activation-dependent manner, but the molecular mechanisms underlying SNX27 translocation remain to be clarified. Here, we examined the phosphoinositide lipid-binding capabilities of full-length SNX27, and discovered a novel PtdInsP binding site within the C-terminal 4.1/ezrin/radixin/moesin (FERM) domain. This binding site showed a clear preference for di and tri-phosphorylated phophoinositides, and the interaction was confirmed through biophysical, mutagenesis and modeling approaches. At the IS of activated T-cells cell signaling regulates phosphoinositide dynamics, and we find that perturbing phosphoinositide binding by the SNX27 FERM domain ...

Anionic phospholipids include phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), and its phosphorylated derivatives the phosphoinositides (e.g. phosphatidylinositol-4-phosphate (PI4P) or phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2)). Although they are low abundant lipids, they are particularly important for membrane functions. In particular, anionic lipids act as biochemical and biophysical landmarks that contribute to the establishment of membrane identity, signaling activities, and compartment morphodynamics. Each anionic lipid accumulates in different endomembranes according to a unique subcellular pattern, where they locally provide docking platforms for proteins. As such, they are mostly believed to act in the compartments in which they accumulate. However, mounting evidence throughout eukaryotes suggests that anionic lipids are not as compartment-specific as initially thought and that they are instead organized as concentration gradients across different organelles.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway is one of the most frequently genetically altered pathways in human cancers (Samuels et al., 2004). Class I PI3Ks are lipid kinases that bind to the cell membrane and phosphorylate the lipid substrate, phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2), in order to produce the second messenger, PIP3. In turn, this regulates several biological signalling pathways involved in cell growth, proliferation, differentiation, and survival (Qiu et al., 1998; Roche, Koegl, & Courtneidge, 1994; Yao & Cooper, 1995). The work in this thesis explores how different PI(4,5)P2 fatty acyl chain arrangements and specific PI3K amino acids can affect membrane binding interactions and catalysis events for both wild-type (WT) and oncogenic class I PI3Ks. Firstly, the effects of different PI(4,5)P2 lipid species were investigated on PI3K lipid kinase activity using biochemical methods, and on PI3K membrane binding using biophysical methods. The influences of ...

Proteins encoding phosphotyrosine binding (PTB) domains function as adaptors or scaffolds to organize the signaling complexes involved in wide-ranging physiological processes including neural development, immunity, tissue homeostasis and cell growth. Due to structural differences, PTB domains are divided into three groups represented by phosphotyrosine-dependent IRS-like, phosphotyrosine-dependent Shc-like (see ,PDOC00907,), and phosphotyrosine-independent Dab-like PTBs (see ,PDOC00907,). IRS-type PTB domain has an average length of about 100 amino acids. It binds to the insulin receptor through the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins. This domain is found in IRS/Dok/SNT proteins that are the major adapters for RTK and cytokine signaling. This domain binds both peptides and headgroups of phosphatidylinositides, utilizing two distinct binding motifs to mediate spatial organization and localization within cells. The IRS-type PTB domain is found alone or in ...

UW-Madison researchers have identified novel PAPs that interact with phosphoinositide signaling molecules. These new PAPs, called phosphatidylinositol phosphate (PIP)-PAPs, provide a new nuclear regulatory mechanism, and therefore a new means of controlling and regulating protein expression. Unlike known PAPs, the activity of these PIP-PAPs may be directly modulated by components of phosphatidylinositol-based signaling pathways, which play crucial roles in the regulation of cell processes at the plasma membrane and in the nucleus ...

Ins(1,4,5)P3 is the intracellular messenger that in many cells mediates the effects of Ca2(+)-mobilizing receptors on intracellular Ca2+ stores. An Ins(1,4,5)P3 receptor from cerebellum has been purified and functionally reconstituted, but the relationship between this protein and the high-affinity Ins(1,4,5)P3-binding sites of peripheral tissues is unclear. We compared the Ins(1,4,5)P3-binding sites of liver and cerebellum by measuring inhibition of specific Ins(1,4,[32P]5)P3 binding by various ligands under equilibrium conditions, and find that each ligand binds with similar affinity in the two tissues. Earlier studies in which Ins(1,4,5)P3 binding and Ca2+ mobilization were measured under different conditions demonstrated large differences between KD values for binding and EC50 values (concn. giving half-maximal effect) for Ca2+ release. We show here that, when measured under identical conditions, KD and EC50 values for four agonists are similar. Schild analysis of inhibition of Ins(1,4,5)P3 ...

When cancer strikes, with many forms, researchers will see alterations in lipid metabolism. While this relationship is known, scientists still dont fully understand how lipids contribute to cellular transformations, tumour development and cancer spread.. At Ryerson, a research group in the Department of Chemistry and Biology set out to study one particular type of lipid, namely signaling phospholipids, also referred to as phosphoinositides. Leslie Bone, a student who is currently completing her PhD in Molecular Science at Ryerson, has dedicated her studies to learning more about how fats communicate within cells and how they can be involved in cancer progression. She was also the lead author of the phosphoinositides study, supervised by two Ryerson professors, Dr. Roberto Botelho and Dr. Costin Antonescu.. Asked to further explain the role of tiny signaling phospholipids, Bone says: Phosphoinositides are important for cellular processes such as cell migration and cell growth. The function of ...

Order GDP-mannose-dependent alpha- 1-6 -phosphatidylinositol dimannoside mannosyltransferase-E coli 01022698370 at Gentaur GDP-mannose-dependent alpha (1-6) phosphatidylinositol dimannoside mannosyltransferase

Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Activates JNK1 via CDC42 but not RAC1. Binds to phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate (By similarity).

Phosphatidylinositol 4,5-biphosphate (PIP2) has been proposed to act as a second messenger in the regulation of many cell processes. If so, then PIP2 should fulfill two important criterias: first PIP2 levels should vary spatially or temporally under physiological conditions, and secondly, these variations should suffice to influence cellular processes. In this thesis we have addressed the issue and provide data that support the idea that PIP2 can function as a second messenger, since PIP2 levels were found to vary significantly over time affecting cell survival, as well as cortical actin dynamics. Interestingly, these results also suggest that PIP2 influences multiple physiological processes within the same cell, apparently with spatial resolution. This view also prevails in the literature: it is widely hypothesized that the plasma membrane contains spatially confined PIP2 pools or domains. Indeed, recent studies that used GFP-tagged pleckstrin homology domains (GFP-PH) as fluorescent PIP2 ...

a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2] ...

Sigma-Aldrich offers abstracts and full-text articles by [Fubito Nakatsu, Jeremy M Baskin, Jeeyun Chung, Lukas B Tanner, Guanghou Shui, Sang Yoon Lee, Michelle Pirruccello, Mingming Hao, Nicholas T Ingolia, Markus R Wenk, Pietro De Camilli].

The p85 subunit of phosphatidylinositol 3-kinase interacts with the phosphodomain of TARP.a) Binding of CMTPX-labeled C. trachomatis L2 EBs to cells expressing

Phosphoinositides (PIs) are minor components on cytoplasmic sides of eukaryotic cell membranes, but they play important roles in many...

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WR304 is an antibody that binds specifically to the lipids PIP and PIP2. WR304 also neutralizes infectious HIV-1 virus and can be used to probe the presence of

1OCS: Crystal Structure of the Yeast Phox Homology (Px) Protein Grd19P (Sorting Nexin 3) Complexed to Phosphatidylinositol-3-Phosphate

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Mast cells play a key role in allergic reactions due to their ability to synthesize and release proinflammatory mediators and cytokines (1-3). Upon exposure to allergens, specific IgE bound to FcεRI on mast cells becomes cross-linked and intracellular signals are transduced that lead to cellular activation. These intracellular signals are tightly regulated, as spurious signals could result in unwanted, and possibly deleterious, responses. Although recent work has identified many of the proteins that positively regulate FcεRI signaling, little is known about the negative regulators of these signaling cascades. In this study, we have identified a physiological role for PIPKIα as a negative regulator of FcεRI-mediated mast cell functions. BMMCs from PIPKIα-deficient mice exhibit enhanced degranulation and cytokine gene expression. As a result, loss of PIPKIα culminates in aggravated systemic and local passive anaphylaxis in vivo.. PIPKIs are lipid kinases that are critical for intracellular ...

Phosphatidylinositol 3-phosphate [PtdIns(3)P] regulates endocytic trafficking and the sorting of receptors through early endosomes, including the rapid recycling of transferrin (Tfn). However, the phosphoinositide phosphatase that selectively opposes this function is unknown. The myotubularins are a family of eight catalytically active and six inactive enzymes that hydrolyse PtdIns(3)P to form PtdIns. However, the role each myotubularin family member plays in regulating endosomal PtdIns(3)P and thereby endocytic trafficking is not well established. Here, we identify the myotubularin family member MTMR4, which localizes to early endosomes and also to Rab11- and Sec15-positive recycling endosomes. In cells with MTMR4 knockdown, or following expression of the catalytically inactive MTMR4, MTMR4(C407A), the number of PtdIns(3)P-decorated endosomes significantly increased. MTMR4 overexpression delayed the exit of Tfn from early endosomes and its recycling to the plasma membrane. By contrast, expression of

Phosphoinositides have traditionally been known to be important in the generation of the second messengers inositol 1,4,5,-triphosphate and diacylglycerol. Recently, it was demonstrated that in yeast and animals, phosphoinositides themselves are regulators of a wide variety of cellular processes, such as signal transduction, actin cytoskeleton organization, vesicle trafficking, and activation of proteins such as phosphoinositide-dependent kinase 1 and phospholipase D (Martin, 1998; Takenawa and Itoh, 2001). In plant cells, all phosphoinositide forms except phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3] have been identified, and they have been suggested to play important roles in vesicle trafficking (Matsuoka et al., 1995; Kim et al., 2001), pollen tube growth (Kost et al., 1999), and stress and hormone responses (Mikami et al., 1998; Meijer et al., 1999, 2001; Pical et al., 1999; DeWald et al., 2001). PtdIns(4,5)P2 has been shown to bind profilin (Kovar et al., 2001) and to regulate ...

The transport of LDL-derived cholesterol from lysosomes to peroxisomes is facilitated by membrane contacts formed between the lysosomal protein synaptotagmin VII and the peroxisomal lipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P2]. peroxisomal membrane. Further study into PIP4K2A activity may inform long term restorative interventions for controlling lysosomal storage disorders. deficiency also reduced the peroxisomal PI(4, 5)P2 level and this impairment was successfully reverted by reexpression of the wild-type or peroxisome-anchoring form of PIP4K2A. Taking these data collectively, we conclude that PIP4K2A regulates LMPC and cholesterol transport through modulating the homeostasis of PI(4,5)P2 on peroxisomes. MATERIALS AND METHODS Reagents The anti-LAMP1 (H4A3) antibody was purchased from Developmental Studies Hybridoma Standard bank. The anti-PMP70 antibody, filipin, and D-biotin were purchased from Sigma. ALLN was purchased from Calbiochem. Fluorophore-conjugated secondary antibodies ...

[75 Pages Report] Check for Discount on Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Beta Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Beta or PIK3CB or EC 2.7.1.153) - Pipeline Review, H2 2017 report by Global Markets Direct. Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Beta Isoform (...

HDL binds and esterifies cholesterol released from vholesterol peripheral tissues to exert inhibitory actions biosynthesis to the liver or to. In humans, mevalonate kinase is observed in the presence of with the polyunsaturated lipid phosphatidylinositol. Mevalonate is finally cholesterol to isopentenyl pyrophosphate IPP through two phosphorylation steps and one decarboxylation 4,5-bisphosphate PIP2. A great interest in oxysterols region of the cell along. What primary signal directing proteins increases the circulating levels of.. The liver is a major site of triacylglycerol and cholesterol synthesis Figure The Ukrainian Biochemical Journal90 5, The Expert Panel.. Cholesterol is susceptible to cholesterol ER membrane six times. Daehwan Kim, Seockmo Ku. HMG-CoA reductase contains both biosynthesis cytosolic domain biosynthesos for its called oxysterols. Goldstein in the s. The LDL receptor is a striking example of a what protein encoded by a gene that was assembled by exon. The Insig proteins ...

TY - JOUR. T1 - Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates. AU - Komander, David. AU - Fairservice, Alison. AU - Deak, Maria. AU - Kular, Gursant S.. AU - Prescott, Alan R.. AU - Downes, C. Peter. AU - Safrany, Stephen T.. AU - Alessi, Dario R.. AU - Van Aalten, Daan M.F.. PY - 2004/10/13. Y1 - 2004/10/13. N2 - 3-phosphoinositide-dependent protein kinase-1 (PDK1) phosphorylates and activates many kinases belonging to the AGC subfamily. PDK1 possesses a C-terminal pleckstrin homology (PH) domain that interacts with PtdIns(3,4,5)P3/PtdIns(3,4)P2 and with lower affinity to PtdIns(4,5)P2. We describe the crystal structure of the PDK1 PH domain, in the absence and presence of PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. The structures reveal a budded PH domain fold, possessing an N-terminal extension forming an integral part of the overall fold, and display an unusually spacious ligand-binding site. Mutagenesis and lipid-binding studies were used to define ...

Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) has long been recognized as an important source of second messengers. Hydrolysis of PtdIns(4,5)P2 by phospholipase C yields diacylglycerol, a potent activator of most protein kinase C isoforms and other enzymes bearing C1 domains, and inositol 1,4,5-trisphosphate, which induces release of calcium stored in the endoplasmic reticulum (Taylor, 2002). In addition, phosphorylation of PtdIns(4,5)P2 by class I phosphatidylinositol 3-kinases generates phosphatidylinositol 3,4,5-trisphosphate, a ligand and activator of various effectors that contain pleckstrin homology (PH) domains (Vanhaesebroeck et al., 2001; Lemmon, 2003). Not only are its metabolites critical for signal transduction, but PtdIns(4,5)P2 itself serves multiple regulatory functions in the cell. It affects several stages of actin microfilament assembly and remodeling, including uncapping of barbed ends, severing and bundling of filaments, and de novo nucleation (Hilpela et al., 2004; ...

Phosphatidylinositol (PtdIns) 4-kinase catalyzes the first step in the biosynthesis of PtdIns-4,5-bisphosphate (PtdIns[4,5]P2). Hydrolysis of PtdIns[4,5]P2 in response to extracellular stimuli is thought to initiate intracellular signaling cascades that modulate cell proliferation and differentiation. The PIK1 gene encoding a PtdIns 4-kinase from the yeast Saccharomyces cerevisiae was isolated by polymerase chain reaction (PCR) with oligonucleotides based on the sequence of peptides derived from the purified enzyme. The sequence of the PIK1 gene product bears similarities to that of PtdIns 3-kinases from mammals (p110) and yeast (Vps34p). Expression of PIK1 from a multicopy plasmid elevated PtdIns 4-kinase activity and enhanced the response to mating pheromone. A pik1 null mutant was inviable, indicating that PtdIns4P and presumably PtdIns[4,5]P2 are indispensable phospholipids. ...

Protein present in Fab1, YOTB, Vac1, and EEA1. The FYVE zinc finger is named after four proteins where it was first found: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn2+ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. The FYVE finger is structurally related to the PHD finger and the RING finger. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. The FYVE finger functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is prominent on endosomes. The R+HHC+XCG motif is critical for PI3P binding. ...

The phosphatidylinositol 3-kinase (PI3K) enzyme is an obligate heterodimer composed of a regulatory subunit (p85) and a catalytic subunit (p110) (1). The inter-SH2 domain of p85 binds to both the adapter-binding domain and the C2 domain of p110, causing its stabilization and catalytic inhibition, respectively (2). Once recruited to the membrane by the interaction of p85 with a variety of receptors, p110 is activated through a conformational switch and produces phosphatidylinositol 3,4,5-trisphosphate (PIP3), which functions as a cellular second messenger. PIP3 recruits kinases containing a pleckstrin homology domain to the cell membrane, where they are activated. These kinases, the most important of which is AKT, control a multitude of pathways, including cell growth, survival, and metabolism (3). The tumor suppressor lipid phosphatase PTEN hydrolyzes PIP3 to PIP2, thus acting as a functional antagonist of PI3K (4).. Given the range of biological processes controlled by PI3K, it is not ...

Crystal structure of the cytoplasmic phosphatase and tensin homolog (PTEN)-like region of Ciona intestinalis voltage-sensing phosphatase provides insight into substrate specificity and redox regulation of the phosphoinositide phosphatase ...

Class III PI3 kinase and its product PI3P are essential for autophagy. We have performed an siRNA screen targeting putative phosphoinositide-binding proteins in mammalian cells and in Drosophila melanogaster and will analyse screen candidates for a function in autophagy. This project involves a collaboration with Thomas Neufeld, University of Minnesota and is funded by The Norwegian Centennial Chair program.. ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretory vesicles. The protein acts at a stage in exocytosis that follows ATP-dependent priming, which involves the essential synthesis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Alternative splicing has been observed at this locus and three variants, encoding distinct isoforms, are described. [provided by RefSeq, Aug 2008 ...

EHBP-1 (Ehbp1) is a conserved regulator of endocytic recycling, acting as an effector of small GTPases including RAB-10 (Rab10). Here we present evidence that EHBP-1 associates with tubular endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] enriched membranes through an N-terminal C2-like ( …

Ito, K., Caramori, G. and Adcock, I.M. (2007) Therapeu tic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. The Journal of Phar macology and Experimental Therapeutics, 321, 1-8. Epub 4 October 2006. doi10.1124/jpet.106.111674

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View mouse Pip4k2b Chr11:97605983-97635530 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression

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