TY - JOUR. T1 - Inositol polyphosphate multikinase mediates extinction of fear memory. AU - Park, Jina. AU - Longo, Francesco. AU - Park, Seung Ju. AU - Lee, Seulgi. AU - Bae, Mihyun. AU - Tyagi, Richa. AU - Han, Jin Hee. AU - Kim, Seyun. AU - Santini, Emanuela. AU - Klann, Eric. AU - Snyder, Solomon H. PY - 2019/2/12. Y1 - 2019/2/12. N2 - Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by ...
TY - JOUR. T1 - Synthesis of fluorescent phosphatidylinositols using a novel inositol H- phosphonate. AU - Leung, Lawrence W.. AU - Vilchèze, Catherine. AU - Bittman, Robert. PY - 1998/5/7. Y1 - 1998/5/7. N2 - Coupling of 1,2-diradyl-sn-glycerol 5 with the novel inositol H- phosphonate derivative, 6-O-benzyl-2,3:4,5-di-O-isopropylidene-myo-inositol H-phosphonate (3), gave fluorescent analogs of phosphatidylinositol (PtdIns, 1) and PtdIns(4,5)-bisphosphate (PtdIns(4,5)P2, 2). Unlike the corresponding phosphoramidate, 3 was stable at -20 °C for several months, making it a useful intermediate for the synthesis of myo-inositol phospholipids.. AB - Coupling of 1,2-diradyl-sn-glycerol 5 with the novel inositol H- phosphonate derivative, 6-O-benzyl-2,3:4,5-di-O-isopropylidene-myo-inositol H-phosphonate (3), gave fluorescent analogs of phosphatidylinositol (PtdIns, 1) and PtdIns(4,5)-bisphosphate (PtdIns(4,5)P2, 2). Unlike the corresponding phosphoramidate, 3 was stable at -20 °C for several months, ...
Type II phosphatidylinositol (PtdIns) 4-kinases produce PtdIns 4-phosphate, an early key signaling molecule in phosphatidylinositol cycle, which is indispensable for T cell activation. Type II PtdIns 4-kinase alpha and beta have similar biochemical properties. To distinguish these isoforms Epigallocatechin gallate (EGCG) has been evaluated as a specific inhibitor. EGCG is the major active catechin in green tea having anti-inflammatory, antiatherogenic and cancer chemopreventive properties. The precise mechanism of actions and molecular targets of EGCG in early signaling cascades are not well understood. In the present study, we have shown that EGCG inhibits type II PtdIns 4-kinases (alpha and beta isoforms) and PtdIns 3-kinase activity in vitro. EGCG directly bind to both alpha and beta isoforms of type II PtdIns 4-kinases with a Kd of 2.62 mu M and 1.02 mu M, respectively. Type II PtdIns 4-kinase-EGCG complex have different binding pattern at its excited state. Both isoforms showed significant ...
Pantothenate kinase-associated neurodegeneration is a form of neurodegeneration with brain iron accumulation, characterized by a progressive movement disorder and prominent iron deposition in the globus pallidus. Formerly referred to as Hallervorden-Spatz syndrome, the disorder was renamed pantothenate kinase-associated neurodegeneration after discovery of the causative gene, PANK2. Although the pathological features of clinically characterized Hallervorden-Spatz syndrome have been described, the literature is confounded by the historical use of this term for nearly all conditions with prominent basal ganglia iron accumulation and by the fact that this term encompasses a genetically heterogeneous group of disorders, now referred to as 'neurodegeneration with brain iron accumulation'. As a result, interpreting reports that precede molecular characterization of specific forms of neurodegeneration with brain iron accumulation is problematic. In the present studies, we describe neuropathological ...
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 ...
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.
The effect of oxytocin on phosphoinositide metabolism as well as on membrane protein phosphorylation in myometrial tissue was studied. Oxytocin enhanced the 32P incorporation into phospholipids in myometrial tissue. The effect of oxytocin on phosphoinositide metabolism was also detected in plasma membrane of 20 days pregnant rats. Phosphorylated membrane lipids have been analysed and phosphatidylinositol 4, 5-bisphosphate proved to be the main reaction product. Oxytocin enhanced the 32P incorporation into phospholipids measured in the first 30 sec then the labeling decreased more rapidly then in case of the control. The effect of oxytocin proved to be concentration dependent. The protein phosphorylation was also influenced by oxytocin. However the amount of alkylphosphate formed depended on the presence or absence of Ca2+, Ca2+-calmodulin and cyclic AMP, oxytocin influenced the protein phosphorylation in the presence of Ca2+-calmodulin only.
Establishment of anoikis-resistant cell model in vitro is usually on the basis of suspension culture that prevents cells from attachment (23-25). Therefore, we chose ultra-low attachment plates for the continuous suspension culture of the parental ACHN cells for 10 days, and the re-adherent cells were regarded as anoikis-resistant ACHN cells. Our data revealed that anoikis-resistant ACHN cells were characterized with more aggressive malignant biological behavior, including more rapid proliferation, less detachment-induced apoptosis and more capable of invasion in contrast to parental cells.. The molecular mechanisms involved in anoikis-resistance have been extensively investigated. PI3Ks are a family of lipid kinases that phosphorylate the 3′-OH group on phosphatidylinositols in the plasma membrane, resulting in recruitment of Akt to cell membrane for activation, which regulates tumor growth and survival (26). Likewise, MEK/ERK is the most typical mitogen activated protein kinase (MAPK) ...
Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.. Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).. During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. ...
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 ...
NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn ...
TY - JOUR. T1 - Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNS. AU - Mantyh, P. W.. AU - Pinnock, R. D.. AU - Downes, C. P.. AU - Goedert, M.. AU - Hunt, S. P.. PY - 1984/12/1. Y1 - 1984/12/1. N2 - The undecapeptide substance P is a neurotransmitter candidate in the mammalian central and peripheral nervous system1. Although the distribution of substance P-like immunoreactivity within the central nervous system (CNS) is well established2, the recent identification and autoradiographic localization of specific substance P-binding sites has revealed numerous areas of mismatch between peptide levels and numbers of such sites3-6. Previous studies have shown that substance P stimulates the hydrolysis of inositol phospholipids in peripheral tissues and in the hypothalamus7,8, probably through stimulation of a polyphosphoinositide-specific phospholipase C (refs 9-11). Inositol phospholipid hydrolysis has been implicated in the mobilization of cytosolic calcium ...
Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Alpha Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Alpha or Phosphoinositide 3 Kinase Catalytic Alpha Polypeptide or Serine/Threonine Protein Kinase PIK3CA or PIK3CA or EC 2.7.11.1 or EC 2.7.1.153) - The phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha also called p110α is a protein encoded by the PIK3CA gene. It is involved in cell growth, survival, proliferation, motility and morphology. It participates in cellular signaling in response to various growth factors. It is involved in the activation of AKT1 and signaling via insulin receptor substrate (IRS) proteins. It is essential in endothelial cell migration during vascular development through VEGFA signaling. It is required for lymphatic vasculature development.. Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Alpha Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Alpha ...
Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the FREQ gene in humans. NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-myristoyl-switch proteins. NCS-1 regulates synaptic transmission, helps control the dynamics of nerve terminal growth, is critical for some forms of learning and memory in C. elegans and mammals, regulates corticohippocampal plasticity; and enhancing levels of NCS-1 in the mouse dentate gyrus increases spontaneous exploration of safe environments, potentially linking NCS-1 to curiosity. NCS-1 is a calcium sensor, not a calcium buffer (chelator); thus it is a high-affinity, low-capacity, calcium-binding protein. Frq can substitute for calmodulin in some situations. It is thought to be associated with neuronal secretory vesicles and regulate neurosecretion. It is the Ca2+-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase, PIK1 It binds to many ...
Mevalonate kinase deficiency (MKD) is a recessively inherited autoinflammatory disorder with a spectrum of manifestations, including the well-defined clinical phenotypes of hyperimmunoglobulinemia D and periodic fever syndrome and mevalonic aciduria. Patients with MKD have recurrent attacks of hyperinflammation associated with fever, abdominal pain, arthralgias, and mucocutaneous lesions, and more severely affected patients also have dysmorphisms and central nervous system anomalies. MKD is caused by mutations in the gene encoding mevalonate kinase, with the degree of residual enzyme activity largely determining disease severity. Mevalonate kinase is essential for the biosynthesis of nonsterol isoprenoids, which mediate protein prenylation. Although the precise pathogenesis of MKD remains unclear, increasing evidence suggests that deficiency in protein prenylation leads to innate immune activation and systemic hyperinflammation. Given the emerging understanding of MKD as an autoinflammatory disorder,
At fertilization in mammals, the sperm triggers a series of low-frequency cytosolic Ca2+ oscillations that continue for several hours ( Cuthbertson and Cobbold, 1985; Kline and Kline, 1992). This Ca2+ signal is responsible for the exocytosis of cortical granules, resumption of meiosis and activation of development ( Kline and Kline, 1992; Miyazaki et al., 1993; Xu et al., 1994; Abbott and Ducibella, 2001). In mammals, the main intracellular Ca2+ channel involved in Ca2+ release at fertilization is the type I Ins(1,4,5)P3-receptor [Ins(1,4,5)P3R]. It is present far in excess of the other isoforms ( Jellerette et al., 2000; Brind et al., 2000) and injection of functionally inhibitory antibodies or downregulation of the receptor during maturation, both lead to an inhibition of fertilization-induced Ca2+ transients ( Miyazaki et al., 1993; Brind et al., 2000). Thus, Ca2+ release and egg activation at fertilization is triggered by Ins(1,4,5)P3 production.. Ins(1,4,5)P3 is generated via phospholipase ...
Regulates the phosphatidylinositol (4,5)-diphosphate levels on the cytoplasmic surface of the endoplasmic reticulum and thereby regulates secretion. Does not utilize phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), nor phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 4-phosphate (PtdIns(4)P).
PIPKIβ knockdown inhibits dHL60 cell polarization and chemotaxis. (A) PIPKIβ knockdown in dHL60 cells 48 h after transfection with 50 nM control or PIPKIβ-specific siRNA, as determined by quantitative RT-PCR (see Materials and methods). The results are normalized to the relative PIPKIβ mRNA levels in cells transfected with control siRNA (representative of five experiments). (B) Crude lysates (80 μg/lane) from cells as in A were analyzed by immunoblot with anti-PIPKIβ and anti-actin antibodies. The graph represents mean ± SEM of densitometry values for the PIPKIβ band from three independent experiments, taking the band in siRNA control cells as 100%. (C) Cell polarity depends on PIPKIβ. Uniformly stimulated dHL60 cells transfected with control or two PIPKIβ-specific siRNA were stained with phalloidin (red) and phospho-ERM proteins (green) as leading edge and uropod markers, respectively. Only cells showing clear segregation of phalloidin and phospho-ERM proteins were scored as ...
MARCKS (myristoylated alanine-rich C kinase substrate) is a major cytoskeletal protein substrate of PKC (protein kinase C) whose cellular functions are still unclear. However numerous studies have implicated MARCKS in the stabilization of cytoskeletal structures during cell differentiation. The present study was performed to investigate the potential role of Ca2+-dependent proteinases (calpains) during myogenesis via proteolysis of MARCKS. It was first demonstrated that MARCKS is a calpain substrate in vitro. Then, the subcellular expression of MARCKS was examined during the myogenesis process. Under such conditions, there was a significant decrease in MARCKS expression associated with the appearance of a 55 kDa proteolytic fragment at the time of intense fusion. The addition of calpastatin peptide, a specific calpain inhibitor, induced a significant decrease in the appearance of this fragment. Interestingly, MARCKS proteolysis was dependent of its phosphorylation by the conventional PKCα. ...
Further evaluation of PI3K/AKT/mTOR pathway inhibitors is required to confirm whether the patterns of sensitivity observed in preclinical studies can be applied in the clinic. Although many early-phase trials have independently failed to identify a distinct association between clinical response and the most common alterations in the PI3K pathway (PIK3CA mutation and PTEN loss), a pooled analysis of 140 patients with various breast and gynecologic cancers treated with different PI3K/AKT/mTOR inhibitors identified an increased rate of RECIST-defined clinical responses among patients with PIK3CA mutations (75). A follow-up study pooling 1,012 patients with diverse cancers treated with PI3K/AKT/mTOR pathway inhibitors also identified an increased rate of response among tumors with PIK3CA H1047R mutation, but not those with other PIK3CA mutations or concurrent PIK3CA and KRAS mutations (76). The findings of these association studies have sparked interest in the research community; however, additional ...
In bovine adrenal chromaffin cells, prostaglandin E2 (PGE2) stimulates the formation of inositol phosphates and Ca2+ mobilization through its specific receptor [Yokohama, Tanaka, Ito, Negishi, Hayashi & Hayaishi (1988) J. Biol. Chem. 263, 1119-1122]. Here we show that PGE2-induced phosphoinositide metabolism was blocked by pretreatment with 12-O-tetradecanoylphorbol 13-acetate (TPA). Using intact cells, we also examined the inhibitory effect of TPA on the individual steps of the activation process of phosphoinositide metabolism. The inhibition was observed within 1 min and complete by 10 min after addition of 1 microM-TPA, and half-maximal inhibition by TPA occurred at 20 nM. TPA prevented Ca2+ mobilization induced by PGE2, but not by the Ca2+ ionophore ionomycin. The inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate did not inhibit the formation of inositol phosphates and Ca2+ mobilization by PGE2. TPA treatment affected neither the high-affinity binding of [3H]PGE2 to intact cells and ...
Background: Although suicide is a leading cause of death in the United States and represents a significant public health threat, little is known about the neurobiological or molecular factors that contribute to its pathophysiology. A number of studies now indicate that lithium has considerable efficacy in the prevention of suicide in patients with affective disorders, and accumulating evidence indicates that protein kinase C (PKC) and its substrates, in particular the myristoylated alanine-rich C kinase substrate (MARCKS), are primary targets of chronic lithium treatment. We therefore hypothesized that a dysregulation in MARCKS expression in key brain regions could contribute to the pathophysiology associated with suicide. To address this, we examined MARCKS, as well as the closely related MARCKS-related protein (MRP), mRNA expression in the hippocampus and dorsolateral prefrontal cortex of suicide victims and normal controls. Method: MARCKS and MRP mRNA expression was assessed by quantitative ...
Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency. ...
Murine D type cyclins associate with a catalytic subunit (p34PSK-J3) with properties distinct from known cyclin-dependent kinases (cdks). Mouse p34PSK-J3 shows less than 50% amino acid identity to p34cdc2, p33cdk2, and p36cdk3, lacks a PSTAIRE motif, and does not bind to p13suc1. Cyclin D1-p34PSK-J3 …
The effects of Li+ on carbachol-stimulated phosphoinositide metabolism were examined in rat cerebral-cortex slices labelled with myo-[2-3H]inositol. The muscarinic agonist carbachol evoked an enhanced steady-state accumulation of [3H]inositol monophosphate ([3H]InsP1), [3H]inositol bisphosphate ([3H]InsP2), [3H]inositol 1,3,4-trisphosphate ([3H]Ins(1,3,4)P3), [3H]inositol 1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) and [3H]inositol tetrakisphosphate ([3H]InsP4). Li+ (5 mM), after a 10 min lag, severely attenuated carbachol-stimulated [3H]InsP4 accumulation while simultaneously potentiating accumulation of both [3H]InsP1 and [3H]InsP2 and, at least initially, of [3H]Ins(1,3,4)P3. These data are consistent with inhibition of inositol mono-, bis- and 1,3,4-tris-phosphate phosphatases to different degrees by Li+ in brain, but are not considered to be completely accounted for in this way. Potential direct and indirect mechanisms of the inhibitory action of Li+ on [3H]InsP4 accumulation are considered. The ...
BioAssay record AID 277735 submitted by ChEMBL: Antagonist potency at human bradykinin B2 receptor assessed as effect on inositol monophosphate accumulation in CHOdhfr- cells.
In isolated rat hepatocytes, vasopressin evoked a large increase in the incorporation of [32P]Pi into phosphatidylinositol, accompanied by smaller increases in the incorporation of [1-14C]oleate and [U-14C]glycerol. Incorporation of these precursors into the other major phospholipids was unchanged during vasopressin treatment. Vasopressin also promoted phosphatidylinositol breakdown in hepatocytes. Half-maximum effects on phosphatidylinositol breakdown and on phosphatidylinositol labelling occurred at about 5 nM-vasopressin, a concentration at which approximately half of the hepatic vasopressin receptors are occupied but which is much greater than is needed to produce half-maximal activation of glycogen phosphorylase. Insulin did not change the incorporation of [32P]Pi into the phospholipids of hepatocytes and it had no effect on the response to vasopressin. Although the incorporation of [32P]Pi into hepatocyte lipids was decreased when cells were incubated in a Ca2+-free medium, vasopressin ...
Consistent signalling via the PI3K/AKT/mTOR pathway is usually a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects around the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors CUDC-907 inhibition is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further CUDC-907 inhibition suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a encouraging treatment option that should be further analysed in an experimental MPNST mouse model in vivo. (enhances RAS-dependent and subsequent activation of the mitogen-activated protein kinase (MAPK) pathway and the PI3K/AKT/mTOR pathway, ...
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 synaptojanin's inositol 5′-phosphatase domain). These results strongly indicate that enhanced clathrin coat ...
TY - JOUR. T1 - Inhibition of receptor-coupled phosphoinositide hydrolysis by sulfur-containing amino acids in rat brain slices. AU - Li, Xiaohua. AU - Jope, Richard S. PY - 1989/9/1. Y1 - 1989/9/1. N2 - Sulfur-containing amino acids were found to inhibit norepinephrine-stimulated [3H]phosphoinositide hydrolysis in rat cortical slices. Of the amino acids tested, l-cysteine was the most potent, inhibiting the response by 42 and 85% at concentrations of 50 and 500 μM respectively. l-Cystine and l-serine-O-sulfate also inhibited the response to norepinephrine, but to a lesser degree than did l-cysteine. l-homocysteic acid slightly potentiated phosphoinositide hydrolysis at a concentration of 100μm, but caused inhibition at 500 μM. l-cysteine sulfinate produced effects intermediate to those of l-cysteine and l-homocysteic acid, having no effect on the response to norepinephrine at 50 μM, but causing 84% inhibition at 500 μM. The d-isomers of cysteine and homocysteic acid were much less potent ...
immune Uncategorized PP121, Rabbit polyclonal to BMPR2 Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate diverse cellular procedures including PP121 proliferation adhesion success and motility. III tests in individuals with advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma. With this review we summarized the main substances of PI3K signaling pathway and talked about the preclinical versions and clinical tests of powerful small-molecule PI3K inhibitors. Intro Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play central part in rules of cell routine apoptosis DNA restoration senescence angiogenesis mobile rate of metabolism and motility [1]. They become intermediate signaling substances PP121 and are renowned for their jobs in the PI3K/AKT/mTOR signaling pathway [2 3 PI3Ks transmit indicators through the cell surface towards the cytoplasm by producing second messengers - phosphorylated phosphatidylinositols - which activate multiple effector ...
K04526 INS; insulin K04527 INSR; insulin receptor [EC:2.7.10.1] K16172 IRS1; insulin receptor substrate 1 K16172 IRS1; insulin receptor substrate 1 K07187 IRS2; insulin receptor substrate 2 K07187 IRS2; insulin receptor substrate 2 K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K06276 PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04456 AKT; RAC ...
TY - JOUR. T1 - Membrane-targeted phosphatidylinositol 3-kinase mimics insulin actions and induces a state of cellular insulin resistance. AU - Egawa, Katsuya. AU - Sharma, Prem M.. AU - Nakashima, Naoki. AU - Huang, Yi. AU - Huver, Evana. AU - Boss, Gerry R.. AU - Olefsky, Jerrold M.. PY - 1999/5/14. Y1 - 1999/5/14. N2 - Phosphatidylinositol (PI) 3-kinase plays an important role in various insulin-stimulated biological responses including glucose transport, glycogen synthesis, and protein synthesis. However, the molecular link between PI 3- kinase and these biological responses is still unclear. We have investigated whether targeting of the catalytic p110 subunit of PI 3-kinase to cellular membranes is sufficient and necessary to induce PI 3-kinase dependent signaling responses, characteristic of insulin action. We overexpressed Myc- tagged, membrane-targeted p110 (p110(CAAX)), and wild-type p110 (p110(WT)) in 3T3-L1 adipocytes by adenovirus-mediated gene transfer. Overexpressed p110(CAAX) ...
The effect of long-term ethanol exposure on muscarinic receptors was investigated in human neuroblastoma SH-SY5Y cells. Exposure to 100 mM ethanol for 4 days enhanced both peak and steady-state levels of carbachol-stimulated inositol 1,4,5-bisphosphate increase. An ethanol concentration of 50 mM was sufficient for an enhancement of this event. The carbachol-stimulated decrease in [3H]inositol-labeled [3H]phosphatidylnositol 4,5-bisphosphate and increase [3H]inositol trisphosphate and [3H]inositol bisphosphate were also potentiated in ethanol-treated cells, which demonstrated that the receptor-stimulated activation of phospholipase C is augmented. Experiments with pirenzepine showed that carbachol-stimulated inositol 1,4,5-trisphosphate increase is mediated via M1 receptors both in ethanol-treated and control cells. Ethanol exposure for 2 or 4 days also caused an increase in [3H]N-methylscopolamine and [3H]quinuclidinyl benzilate binding sites and elevation of [3H]pirenzepine binding, which ...
TY - JOUR. T1 - High-Resolution Structure of the Pleckstrin Homology Domain of Protein Kinase B/Akt Bound to Phosphatidylinositol (3,4,5)-Trisphosphate. AU - Thomas, Christine C.. AU - Deak, Maria. AU - Alessi, Dario R.. AU - van Aalten, Daan M. F.. PY - 2002/7/23. Y1 - 2002/7/23. N2 - The products of PI 3-kinase activation, PtdIns(3,4,5)P3 and its immediate breakdown product PtdIns(3,4)P2, trigger physiological processes, by interacting with proteins possessing pleckstrin homology (PH) domains [1, 2]. One of the best characterized PtdIns(3,4,5)P3/PtdIns(3,4)P2 effector proteins is protein kinase B (PKB), also known as Akt [3-5]. PKB possesses a PH domain located at its N terminus, and this domain binds specifically to PtdIns(3,4,5)P3 and PtdIns(3,4)P2 with similar affinity [6, 7]. Following activation of PI 3-kinase, PKB is recruited to the plasma membrane by virtue of its interaction with PtdIns(3,4,5)P3/PtdIns(3,4)P2 [8-10]. PKB is then activated by the 3-phosphoinositide-dependent pro-tein ...
Sphingosine kinase 1 (SphK1) is a lipid kinase with important roles including regulation of cell survival. We have previously shown reduced SphK1 activity in cells with an established dengue virus type-2 (DENV-2) infection. In this study, we examined the effect of alterations in SphK1 activity on DENV-2 replication and cell death and determined the mechanisms of the reduction in SphK1 activity. Chemical inhibition or overexpression of SphK1 after established DENV-2 infection had no effect on infectious DENV-2 production, although inhibition of SphK1 resulted in enhanced DENV-2-induced cell death. Reduced SphK1 activity was observed in multiple cell types, regardless of the ability of DENV-2 infection to be cytopathic, and was mediated by a post-translational mechanism. Unlike bovine viral diarrhea virus, where SphK1 activity is decreased by the NS3 protein, SphK1 activity was not affected by DENV-2 NS3 but, instead, was reduced by expression of the terminal 396 bases of the 3′ UTR of DENV-2 RNA. We
Few studies on screening of the enzyme phosphatidylinositol-specific phospholipase C (PI-PLC) have been reported. Here we present a simple potato-based med
Order Aspergillus clavatus Phosphatidylinositol transfer protein sfh5 sfh5 -Mammalian Cell 01022755170 at Gentaur Aspergillus clavatus Phosphatidylinositol transfer protein sfh5 (sfh5) Mammalian
Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling has been found in several types of human cancer, including hepatocellular carcinoma (HCC). NVP-BEZ235 is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against HCC in preclinical models. Autophagy is a cellular lysosomal degradation pathway essential for the regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mTOR signaling and often counteracts the efficacy of certain cancer therapeutic agents. In this study, we explored the role of autophagy in apoptosis induced by NVP-BEZ235 in two HCC cell lines, Hep3B and PLC/PRF/5, and identified the mechanism of combinatorial treatment. NVP-BEZ235 was effective in inhibiting the growth of the two HCC cell lines possibly though induction of apoptosis. NVP-BEZ235 also potently increased the expression of LC3-II and decreased the expression of p62, indicating ...
TY - JOUR. T1 - A revised biosynthetic pathway for phosphatidylinositol in Mycobacteria. AU - Morii, Hiroyuki. AU - Ogawa, Midori. AU - Fukuda, Kazumasa. AU - Taniguchi, Hatsumi. AU - Koga, Yosuke. PY - 2010/11/1. Y1 - 2010/11/1. N2 - For the last decade, it has been believed that phosphatidylinositol (PI) in mycobacteria is synthesized from free inositol and CDP-diacylglycerol by PI synthase in the presence of ATP. The role of ATP in this process, however, is not understood. Additionally, the PI synthase activity is extremely low compared with the PI synthase activity of yeast. When CDP-diacylglycerol and [ 14C]1L-myo-inositol 1-phosphate were incubated with the cell wall components of Mycobacterium smegmatis, both phosphatidylinositol phosphate (PIP) and PI were formed, as identified by fast atom bombardment-mass spectrometry and thin-layer chromatography. PI was formed from PIP by incubation with the cell wall components. Thus, mycobacterial PI was synthesized from CDP-diacylglycerol and ...
Commander PIP4K2C anticorps monoclonal et polyclonal pour beaucoup d'applications. Selection de fournisseur de qualité pour anti-PIP4K2C anticorps.
Phosphoinositide-dependent protein kinase 1 (PDK1) is a protein kinase that phosphorylates and activates several other protein kinases from the AGC group (which includes PKA, PKG and PKC), to which PDK1 also belongs. Recent data suggests that PDK1 specificity is achieved by regulation of its interac …
Protein kinase B (PKB) isoforms became activated [and glycogen synthase kinase-3 (GSK3) became inhibited] when mouse Swiss 3T3 fibroblasts were exposed to oxidative stress (H2O2) or heat shock, but not when they were exposed to osmotic shock (0.5 M sorbitol or 0.7 M NaCl), chemical stress (sodium arsenite), the protein-synthesis inhibitor anisomycin, or UV radiation. In contrast, all seven stimuli activated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2). The activation of MAPKAP-K2 was suppressed by the drug SB 203580, but not by inhibitors of phosphoinositide (phosphatidylinositide, PI) 3-kinase. In contrast, the activation of PKB isoforms and the inhibition of GSK3 by oxidative stress or heat shock were prevented by inhibitors of PI 3-kinase, but not by SB 203580. Thus the activation of PKB by oxidative stress or heat shock is mediated by PI 3-kinase and not by MAPKAP-K2. PKBα and PKBγ were also activated by heat shock and oxidative stress in human embryonic kidney ...
In eukaryotes, calcium signalling has been linked to hydrolysis of the phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). The final enzyme in the synthesis of this phosphoinositide, a Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K), is activated by the small G protein ADP-ribosylation factor 1 (ARF1). In mammals, the ARF-PIP5K pathway is a key regulator of cell motility, secretion and cell signalling. We report the characterisation of a unique, putative bifunctional PIP5K in the human malaria parasite Plasmodium falciparum. The protein comprises a C-terminal, functional PIP5K domain with catalytic specificity for phosphatidylinositol 4-phosphate. The recombinant enzyme is activated by ARF1 but not phosphatidic acid. The protein also incorporates an unusual N-terminal domain with potential helix-loop-helix EF-hand-like motifs that is a member of the neuronal calcium sensor family (NCS). Intriguingly, NCS-1 has been shown to stimulate phosphatidylinositol 4-phosphate synthesis by ...
Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P
Actin cytoskeleton remodeling requires the coordinated action of a large number of actin binding proteins that reorganize the actin cytoskeleton by promoting polymerization, stabilizing filaments, causing branching, or crosslinking filaments. Palladin is a key cytoskeletal actin binding protein whose normal function is to enable cell motility during development of tissues and organs of the embryo and in wound healing, but palladin is also responsible for regulating the ability of cancer cells to become invasive and metastatic. The membrane phosphoinositide phosphatidylinositol (PI) 4,5-bisphosphate [PI(4,5)P-2] is a well-known precursor for intracellular signaling and a bona fide regulator of actin cytoskeleton reorganization. Our results show that two palladin domains [immunoglobulin (Ig) 3 and 34] interact with the head group of PI(4,5)P-2 with moderate affinity (apparent K-d = 17 mu M). Interactions with PI(4,5)P-2 decrease the actin polymerizing activity of Ig domain 3 of palladin ...
The family of PI3Ks (phosphatidylinositol 3-kinases) was discovered several decades ago, but until now most attention has been given to class I PI3Ks, mainly due to their previously established role in human disorders such as cancer and metabolic diseases. Class II PI3K has therefore been a bit in the shadow of the more intensively studied other families. Nevertheless, the number of reports about class II has started to increase over the past few years and we are now beginning to gain a clearer picture about the role of class II enzymes in different cellular functions and their involvement in human diseases. The fact that class II PI3K generates different second messengers (phosphoinositides) than the other PI3K family members, gives an indication that these enzymes might play a specific role in the regulation of distinct cellular functions. However, there is still a lot to be learned about the molecular mechanism of activation, the cellular function and the physiological and pathological role ...
Voltage-gated calcium (Cav) channels, which are regulated by membrane potential, cytosolic Ca2+, phosphorylation, and membrane phospholipids, govern Ca2+ entry into excitable cells. Cav channels contain a pore-forming α1 subunit, an auxiliary α2δ subunit, and a regulatory β subunit, each encoded by several genes in mammals. In addition to a domain that interacts with the α1 subunit, β2e and β2a also interact with the cytoplasmic face of the plasma membrane through an electrostatic interaction for β2e and posttranslational acylation for β2a. We found that an increase in cytosolic Ca2+ promoted the release of β2e from the membrane without requiring substantial depletion of the anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) from the plasma membrane. Experiments with liposomes indicated that Ca2+ disrupted the interaction of the β2e amino-terminal peptide with membranes containing PIP2. Ca2+ binding to calmodulin (CaM) leads to CaM-mediated inactivation of Cav currents. ...
[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 (...
TY - JOUR. T1 - Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6- induced neuroendocrine differentiation of prostate cancer cells. AU - Qiu, Y.. AU - Robinson, D.. AU - Pretlow, T. G.. AU - Kung, H. J.. PY - 1998/3/31. Y1 - 1998/3/31. N2 - Etk/Bmx is the newest member of Btk tyrosine kinase family that contains a pleckstrin homology domain, an src homology 3 domain, an src homology 2 domain, and a catalytic domain. Unlike other members of the Btk family kinases, which are mostly hemopoietic cell-specific, Etk/Bmx is preferentially expressed in epithelial and endothelial cells. We first identified this kinase in prostate cancer [Robinson, D., He, F, Pretlow, T. and Kung, H. J. (1996) Proc. Natl. Acad. Sci. USA 93, 5958-5962). Here we report that Etk is engaged in phosphatidylinositol 3-kinase (PI3-kinase) pathway and plays a pivotal role in interleukin 6 (IL-6) signaling in a prostate cancer cell line, ...