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  1. Article ; Online: Research progress on phosphatidylinositol 4-kinase inhibitors.

    Li, Gang / Wu, Yanting / Zhang, Yali / Wang, Huamin / Li, Mengjie / He, Dengqin / Guan, Wen / Yao, Hongliang

    Biochemical pharmacology

    2023  Volume 220, Page(s) 115993

    Abstract: Phosphatidylinositol 4-kinases (PI4Ks) could phosphorylate phosphatidylinositol (PI) to produce ... phosphatidylinositol 4-phosphate (PI4P) and maintain its metabolic balance and location. PI4P, the most abundant ... viruses, and the development of tumors and nervous system diseases. The development of novel ...

    Abstract Phosphatidylinositol 4-kinases (PI4Ks) could phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P) and maintain its metabolic balance and location. PI4P, the most abundant monophosphate inositol in eukaryotic cells, is a precursor of higher phosphoinositols and an essential substrate for the PLC/PKC and PI3K/Akt signaling pathways. PI4Ks regulate vesicle transport, signal transduction, cytokinesis, and cell unity, and are involved in various physiological and pathological processes, including infection and growth of parasites such as Plasmodium and Cryptosporidium, replication and survival of RNA viruses, and the development of tumors and nervous system diseases. The development of novel drugs targeting PI4Ks and PI4P has been the focus of the research and clinical application of drugs, especially in recent years. In particular, PI4K inhibitors have made great progress in the treatment of malaria and cryptosporidiosis. We describe the biological characteristics of PI4Ks; summarize the physiological functions and effector proteins of PI4P; and analyze the structural basis of selective PI4K inhibitors for the treatment of human diseases in this review. Herein, this review mainly summarizes the developments in the structure and enzyme activity of PI4K inhibitors.
    MeSH term(s) Humans ; 1-Phosphatidylinositol 4-Kinase ; Phosphatidylinositol 3-Kinases/metabolism ; Cryptosporidiosis ; Cryptosporidium/metabolism ; Phosphatidylinositol Phosphates ; Phosphatidylinositols/metabolism
    Chemical Substances 1-Phosphatidylinositol 4-Kinase (EC 2.7.1.67) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphatidylinositol Phosphates ; Phosphatidylinositols
    Language English
    Publishing date 2023-12-25
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2023.115993
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  2. Article ; Online: Phosphatidylinositol 3-kinase signaling and immune regulation: insights into disease pathogenesis and clinical implications.

    Nguyen, Tina / Deenick, Elissa K / Tangye, Stuart G

    Expert review of clinical immunology

    2021  Volume 17, Issue 8, Page(s) 905–914

    Abstract: Introduction: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a fundamental role ... immune system. The subsequent identification and characterisation of >300 individuals with a novel immune ... disruptive for immune cell development, activation, differentiation, effector function and self-tolerance ...

    Abstract Introduction: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a fundamental role in cell survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The discovery that germline variants in genes in the PI3K pathway caused inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system. The subsequent identification and characterisation of >300 individuals with a novel immune dysregulatory disorder, termed activated PI3K-delta syndrome (APDS), has reinforced the status of PI3K as a key pathway regulating immune function. Studies of APDS have demonstrated that dysregulated PI3K function is disruptive for immune cell development, activation, differentiation, effector function and self-tolerance, which are all important in supporting effective, long-term immune responses.
    Areas covered: In this review, we recount recent findings regarding humans with germline variants in PI3K genes and discuss the underlying cellular and molecular pathologies, with a focus on implications for therapy in APDS patients.
    Expert opinion: Modulating PI3K immune cell signalling by offers opportunities for therapeutic interventions in settings of immunodeficiency, autoimmunity and malignancy, but also highlights potential adverse events that may result from overt pharmacological or intrinsic inhibition of PI3K function.
    MeSH term(s) Class I Phosphatidylinositol 3-Kinases ; Humans ; Immunologic Deficiency Syndromes/genetics ; Immunologic Deficiency Syndromes/therapy ; Primary Immunodeficiency Diseases/genetics ; Signal Transduction
    Chemical Substances Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
    Language English
    Publishing date 2021-06-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2274260-8
    ISSN 1744-8409 ; 1744-666X
    ISSN (online) 1744-8409
    ISSN 1744-666X
    DOI 10.1080/1744666X.2021.1945443
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  3. Article: Phosphatidylinositol-4-kinase 2α enhances phagosomal TLR signaling and MHC class II presentation in mouse dendritic cells

    Mantegazza, Adriana / Haber, Cynthia Lopez / Marks, Michael

    Molecular immunology. 2022 Oct., v. 150

    2022  

    Abstract: ... phosphatidylinositol (PI)-4-kinase 2α (PI4K2α), which generates PI4P, a lipid reported to engage the TLR adaptor TIRAP ... TLR signaling and anti-bacterial immune responses. We have identified that one such AP-3 effector is ... by increasing membrane surface via tubulation). In summary, PI4K2α is a novel regulator of phagosomal signaling ...

    Abstract Toll like receptor (TLR) recruitment to bacteria-containing phagosomes and subsequent TLR signaling in dendritic cells (DCs) are essential to initiate anti-microbial immune responses, but the mechanisms underlying TLR trafficking to phagosomes are poorly characterized. We previously showed that the endosomal adaptor protein-3 (AP-3) optimizes TLR4 and MyD88 recruitment to phagosomes and favors phagosomal TLR signaling to proinflammatory cytokine secretion, membrane tubulation and MHC-II presentation. However, AP-3 functions indirectly in these activities. We hypothesized that this reflects AP-3’s role in endolysosomal protein sorting, and that defining direct targets of AP-3 sorting will elucidate new membrane pathways controlling TLR signaling and anti-bacterial immune responses. We have identified that one such AP-3 effector is phosphatidylinositol (PI)-4-kinase 2α (PI4K2α), which generates PI4P, a lipid reported to engage the TLR adaptor TIRAP to recruit MyD88 and TIRAP to membranes. We show that PI4K2α is recruited to nascent LPS-bead phagosomes in wild-type (WT) bone marrow-derived (BM) DCs and that its recruitment is reduced in AP-3-deficient pearl BMDCs, both by immunofluorescence microscopy and immunoblotting of isolated phagosomes. Moreover, both PI4K2α-GFP and PI4P co-localize with LPS/OVA-texas red bead phagosomes 2hours after uptake in WT DCs and on phagotubules. The formation of tubules from phagosomes in BMDCs is impaired upon knock-down of PI4K2α but not PI4K2β. This correlates with reduced MHC-II presentation of particulate Ealpha antigen and impaired T cell activation. Additionally, after LPS priming, IL-1β secretion induced by multiple stimuli is reduced in BMDCs by PI4K2α knock-down compared to controls, suggesting that PI4K2α is necessary for optimal inflammasome activity, likely by impacting either priming (via TLR signaling) or NLR stimulation (by increasing membrane surface via tubulation). In summary, PI4K2α is a novel regulator of phagosomal signaling required for TLR recruitment to phagosomes and downstream signaling pathways in DCs.
    Keywords T-lymphocytes ; antigens ; cytokines ; fluorescence microscopy ; immunoblotting ; inflammasomes ; lipids ; mice ; phagosomes ; secretion
    Language English
    Dates of publication 2022-10
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2022.05.042
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  4. Article: Phosphatidylinositol 3-kinase: a novel effector.

    Parker, P J / Waterfield, M D

    Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research

    1992  Volume 3, Issue 10, Page(s) 747–752

    MeSH term(s) Animals ; Cell Division ; Enzyme Activation ; GTP-Binding Proteins/metabolism ; Growth Substances/physiology ; Models, Biological ; Phosphatidylinositol 3-Kinases ; Phosphatidylinositols/metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; Phosphotransferases/genetics ; Phosphotransferases/physiology ; Protein Conformation ; Protein Processing, Post-Translational ; Receptors, Cell Surface/metabolism ; Signal Transduction
    Chemical Substances Growth Substances ; Phosphatidylinositols ; Phosphoproteins ; Receptors, Cell Surface ; Phosphotransferases (EC 2.7.-) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 1992-10
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1034269-2
    ISSN 1044-9523
    ISSN 1044-9523
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    Zs.A 2903: Show issues Location:
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  5. Article ; Online: New phosphatidylinositol 3-kinase inhibitors for cancer.

    Bowles, Daniel W / Jimeno, Antonio

    Expert opinion on investigational drugs

    2011  Volume 20, Issue 4, Page(s) 507–518

    Abstract: ... predictive biomarkers will probably be the key to finding therapeutic uses for this novel class ... conference proceedings to analyze the rationale for targeting PI3K and its downstream effectors in cancer ...

    Abstract Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins important to cancer development or survival. The PI3K signaling axis is an important pathway involved in myriad human malignancies. Inhibition of this axis is a promising therapeutic approach for several cancers.
    Areas covered: This article reviews current literature and recent conference proceedings to analyze the rationale for targeting PI3K and its downstream effectors in cancer. Preclinical and clinical results of several PI3K and PI3K--mammalian target of rapamycin (mTOR) inhibitors in early clinical trials, as single agents and in combination with other drugs, are discussed. Thus far, clinical results have been mixed.
    Expert opinion: The clinical utility of PI3K and PI3K--mTOR inhibitors will depend on appropriate selection of patients. Mutations in the PI3K pathway may predict sensitivity to PI3K inhibition but they are not reliable biomarkers at this point. Efforts to define predictive biomarkers will probably be the key to finding therapeutic uses for this novel class of anticancer agents.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Drugs, Investigational/pharmacology ; Drugs, Investigational/therapeutic use ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Models, Biological ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/physiopathology ; Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Phosphatidylinositol 3-Kinase/genetics ; Phosphatidylinositol 3-Kinase/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/antagonists & inhibitors
    Chemical Substances Antineoplastic Agents ; Drugs, Investigational ; Enzyme Inhibitors ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137)
    Language English
    Publishing date 2011-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1182884-5
    ISSN 1744-7658 ; 0967-8298 ; 1354-3784
    ISSN (online) 1744-7658
    ISSN 0967-8298 ; 1354-3784
    DOI 10.1517/13543784.2011.562192
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    Zs.A 3739: Show issues Location:
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  6. Article ; Online: A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi.

    Hammond, Gerald R V / Machner, Matthias P / Balla, Tamas

    The Journal of cell biology

    2014  Volume 205, Issue 1, Page(s) 113–126

    Abstract: ... to organelle membranes. One member, phosphatidylinositol 4-phosphate (PtdIns4P) has been localized to Golgi ... Polyphosphoinositides are an important class of lipid that recruit specific effector proteins ... membranes based on the distribution of lipid binding modules from PtdIns4P effector proteins ...

    Abstract Polyphosphoinositides are an important class of lipid that recruit specific effector proteins to organelle membranes. One member, phosphatidylinositol 4-phosphate (PtdIns4P) has been localized to Golgi membranes based on the distribution of lipid binding modules from PtdIns4P effector proteins. However, these probes may be biased by additional interactions with other Golgi-specific determinants. In this paper, we derive a new PtdIns4P biosensor using the PtdIns4P binding of SidM (P4M) domain of the secreted effector protein SidM from the bacterial pathogen Legionella pneumophila. PtdIns4P was necessary and sufficient for localization of P4M, which revealed pools of the lipid associated not only with the Golgi but also with the plasma membrane and Rab7-positive late endosomes/lysosomes. PtdIns4P distribution was determined by the localization and activities of both its anabolic and catabolic enzymes. Therefore, P4M reports a wider cellular distribution of PtdIns4P than previous probes and therefore will be valuable for dissecting the biological functions of PtdIns4P in its assorted membrane compartments.
    MeSH term(s) Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; Biosensing Techniques ; COS Cells ; Cell Membrane/metabolism ; Chlorocebus aethiops ; Dogs ; Endosomes/metabolism ; Genes, Reporter ; Golgi Apparatus/metabolism ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Lysosomes/metabolism ; Mice ; Microscopy, Confocal ; Minor Histocompatibility Antigens ; Phosphatidylinositol Phosphates/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; Second Messenger Systems ; Time Factors ; Time-Lapse Imaging ; Transfection ; rab GTP-Binding Proteins/metabolism
    Chemical Substances Bacterial Proteins ; Guanine Nucleotide Exchange Factors ; Luminescent Proteins ; Minor Histocompatibility Antigens ; Phosphatidylinositol Phosphates ; Recombinant Fusion Proteins ; SidM protein, Legionella pneumophila ; phosphatidylinositol 4-phosphate ; rab7 protein (152989-05-4) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; phosphatidylinositol phosphate 4-kinase (EC 2.7.1.67) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2014-04-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Video-Audio Media
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201312072
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  7. Article: Oncogenic Ras blocks anoikis by activation of a novel effector pathway independent of phosphatidylinositol 3-kinase.

    McFall, A / Ulkü, A / Lambert, Q T / Kusa, A / Rogers-Graham, K / Der, C J

    Molecular and cellular biology

    2001  Volume 21, Issue 16, Page(s) 5488–5499

    Abstract: ... mutants or constitutively activated effectors indicated that activation of Raf-1, phosphatidylinositol 3 ... kinase (PI3K), or RalGDS alone is not sufficient to promote Ras inhibition of anoikis. Treatment of Ras ... indicating that extracellular signal-regulated kinase activation contributes to inhibition of anoikis ...

    Abstract Activated Ras, but not Raf, causes transformation of RIE-1 rat intestinal epithelial cells, demonstrating the importance of Raf-independent effector signaling in mediating Ras transformation. To further assess the contribution of Raf-dependent and Raf-independent function in oncogenic Ras transformation, we evaluated the mechanism by which oncogenic Ras blocks suspension-induced apoptosis, or anoikis, of RIE-1 cells. We determined that oncogenic versions of H-, K-, and N-Ras, as well as the Ras-related proteins TC21 and R-Ras, protected RIE-1 cells from anoikis. Surprisingly, our analyses of Ras effector domain mutants or constitutively activated effectors indicated that activation of Raf-1, phosphatidylinositol 3-kinase (PI3K), or RalGDS alone is not sufficient to promote Ras inhibition of anoikis. Treatment of Ras-transformed cells with the U0126 MEK inhibitor caused partial reversion to an anoikis-sensitive state, indicating that extracellular signal-regulated kinase activation contributes to inhibition of anoikis. Unexpectedly, oncogenic Ras failed to activate Akt, and treatment of Ras-transformed RIE-1 cells with the LY294002 PI3K inhibitor did not affect anoikis resistance or growth in soft agar. Thus, while important for Ras transformation of fibroblasts, PI3K may not be involved in Ras transformation of RIE-1 cells. Finally, inhibition of epidermal growth factor receptor kinase activity did not overcome Ras inhibition of anoikis, indicating that this autocrine loop essential for transformation is not involved in anoikis protection. We conclude that a PI3K- and RalGEF-independent Ras effector(s) likely cooperates with Raf to confer anoikis resistance upon RIE-1 cells, thus underscoring the complex nature by which Ras transforms cells.
    MeSH term(s) Animals ; Anoikis/genetics ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Enzyme Activation/genetics ; Gene Expression Regulation ; Genes, ras/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Rats ; Signal Transduction/genetics
    Chemical Substances Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2001-08
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.21.16.5488-5499.2001
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  8. Article: Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors.

    Freeburn, Robin W / Wright, Karen L / Burgess, Steven J / Astoul, Emmanuelle / Cantrell, Doreen A / Ward, Stephen G

    Journal of immunology (Baltimore, Md. : 1950)

    2002  Volume 169, Issue 10, Page(s) 5441–5450

    Abstract: ... phosphoinositide 3-kinase effectors in T lymphocytes. ... high basal levels of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3); the lipid substrate ... 3) and higher levels of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) as well as unsaturated ...

    Abstract The leukemic T cell line Jurkat is deficient in protein expression of the lipid phosphatases Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and phosphatase and tensin homolog deleted on chromosome ten (PTEN). We examined whether the lack of expression of SHIP-1 and PTEN is shared by other leukemic T cell lines and PBLs. Analysis of a range of cell lines and PBLs revealed that unlike Jurkat cells, two other well-characterized T cell lines, namely CEM and MOLT-4 cells, expressed the 5'-phosphatase SHIP at the protein level. However, the 3-phosphatase PTEN was not expressed by CEM or MOLT-4 cells or Jurkat cells. The HUT78 cell line and PBLs expressed both SHIP and PTEN. Jurkat cells exhibited high basal levels of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3); the lipid substrate for both SHIP and PTEN) as well as saturated protein kinase B (PKB) phosphorylation. Lower levels of PI(3,4,5)P(3) and higher levels of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) as well as unsaturated constitutive phosphorylation of PKB were observed in CEM and MOLT-4 cells compared with Jurkat cells. In PBLs and HUT78 cells which express both PTEN and SHIP-1, there was no constitutive PI(3,4,5)P(3) or PKB phosphorylation, and receptor stimuli were able to elicit robust phosphorylation of PKB. Expression of a constitutively active SHIP-1 protein in Jurkat cells was sufficient to reduce both constitutive PKB membrane localization and PKB phosphorylation. Together, these data indicate important differences between T leukemic cells as well as PBLs, regarding expression of key lipid phosphatases. This study provides the first evidence that SHIP-1 can influence the constitutive levels of PI(3,4,5)P(3) and the activity of downstream phosphoinositide 3-kinase effectors in T lymphocytes.
    MeSH term(s) Animals ; Antibodies, Monoclonal/metabolism ; Blood Proteins/metabolism ; CD28 Antigens/immunology ; CD28 Antigens/metabolism ; CD3 Complex/immunology ; CD3 Complex/metabolism ; Cell Membrane/enzymology ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Epitopes, T-Lymphocyte/metabolism ; Humans ; Inositol Phosphates/physiology ; Inositol Polyphosphate 5-Phosphatases ; Jurkat Cells ; Ligands ; Mice ; PTEN Phosphohydrolase ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol Phosphates/metabolism ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ; Phosphatidylinositols/biosynthesis ; Phosphatidylinositols/metabolism ; Phosphoproteins/metabolism ; Phosphoric Monoester Hydrolases/biosynthesis ; Phosphoric Monoester Hydrolases/metabolism ; Phosphoric Monoester Hydrolases/physiology ; Phosphorylation/drug effects ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Receptors, Antigen, T-Cell/physiology ; T-Lymphocyte Subsets/enzymology ; T-Lymphocyte Subsets/metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/biosynthesis ; Tyrosine/metabolism ; src Homology Domains/immunology
    Chemical Substances Antibodies, Monoclonal ; Blood Proteins ; CD28 Antigens ; CD3 Complex ; Enzyme Inhibitors ; Epitopes, T-Lymphocyte ; Inositol Phosphates ; Ligands ; Phosphatidylinositol Phosphates ; Phosphatidylinositols ; Phosphoproteins ; Proto-Oncogene Proteins ; Receptors, Antigen, T-Cell ; Tumor Suppressor Proteins ; phosphatidylinositol 3,4,5-triphosphate ; platelet protein P47 ; inositol 3,4-bisphosphate (23410-61-9) ; Tyrosine (42HK56048U) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; phosphoinositide 5-phosphatase (EC 3.1.3.36) ; Inositol Polyphosphate 5-Phosphatases (EC 3.1.3.56) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; INPP5D protein, human (EC 3.1.3.86) ; INPPL1 protein, human (EC 3.1.3.86) ; Inpp5d protein, mouse (EC 3.1.3.86) ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (EC 3.1.3.86)
    Language English
    Publishing date 2002-10-22
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.169.10.5441
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  9. Article ; Online: RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection.

    Yu, Chien-Hsiung / Micaroni, Massimo / Puyskens, Andreas / Schultz, Thomas E / Yeo, Jeremy Changyu / Stanley, Amanda C / Lucas, Megan / Kurihara, Jade / Dobos, Karen M / Stow, Jennifer L / Blumenthal, Antje

    Journal of immunology (Baltimore, Md. : 1950)

    2015  Volume 195, Issue 8, Page(s) 3890–3900

    Abstract: ... macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton's tyrosine kinase ... by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine ... tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR ...

    Abstract Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105(-/-) macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105(-/-) macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105(-/-) macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA-mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105(-/-) macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105(-/-) macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton's tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.
    MeSH term(s) Animals ; Antigens, CD/genetics ; Antigens, CD/immunology ; Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases/genetics ; Class I Phosphatidylinositol 3-Kinases/immunology ; Enzyme Inhibitors/pharmacology ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/genetics ; MAP Kinase Signaling System/immunology ; Mice ; Mice, Knockout ; Mycobacterium tuberculosis/immunology ; Protein Transport/drug effects ; Protein Transport/genetics ; Protein Transport/immunology ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/immunology ; Purines/pharmacology ; Quinazolinones/pharmacology ; Tuberculosis/genetics ; Tuberculosis/immunology ; Tuberculosis/pathology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/immunology
    Chemical Substances Antigens, CD ; Enzyme Inhibitors ; Ly78 protein, mouse ; Purines ; Quinazolinones ; Tumor Necrosis Factor-alpha ; 1-phosphatidylinositol 3-kinase p110 subunit, mouse (EC 2.7.1.137) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; idelalisib (YG57I8T5M0)
    Language English
    Publishing date 2015-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1500017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Induction of apoptosis and suppression of angiogenesis of hepatocellular carcinoma by HS-159, a novel phosphatidylinositol 3-kinase inhibitor.

    Yun, Sun-Mi / Lee, Ju-Hee / Jung, Kyung Hee / Lee, Hyunseung / Lee, Soyoung / Hong, Sungwoo / Hong, Soon-Sun

    International journal of oncology

    2013  Volume 43, Issue 1, Page(s) 201–209

    Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and ... a novel PI3Kα inhibitor, HS-159 [N-(5-(3-(3-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl ... effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR and P70S6 kinases ...

    Abstract The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer and is emerging as an attractive therapeutic target. In this study, we synthesized a novel PI3Kα inhibitor, HS-159 [N-(5-(3-(3-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide] and evaluated its anticancer effects on Huh-7 human hepatocellular carcinoma (HCC) cells. HS-159 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR and P70S6 kinases in a dose-dependent manner. This compound also induced apoptosis and increased the fraction of apoptotic cells in the sub-G1 phase as well as the levels of cleaved PARP, caspase-3 and -9. Furthermore, HS-159 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor which play important roles in angiogenesis. The anti-angiogenic effect of HS-159 was confirmed by the suppression of tube formation and migration of human umbilical vein endothelial cells in vitro. Collectively, our results demonstrate that HS-159 exhibited anticancer activities including the induction of apoptosis and inhibition of angiogenesis by blocking the PI3K/Akt pathway in Huh-7 cells. Therefore, we suggest that this drug may be potentially used for targeted HCC therapy.
    MeSH term(s) Apoptosis/drug effects ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds, 2-Ring/pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/pathology ; Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Signal Transduction/drug effects ; Sulfonamides/pharmacology
    Chemical Substances Heterocyclic Compounds, 2-Ring ; N-(5-(3-(3-cyanophenyl)imidazo(1,2-a)pyridin-6-yl)pyridin-3-yl)benzenesulfonamide ; Sulfonamides ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137)
    Language English
    Publishing date 2013-07
    Publishing country Greece
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1154403-x
    ISSN 1791-2423 ; 1019-6439
    ISSN (online) 1791-2423
    ISSN 1019-6439
    DOI 10.3892/ijo.2013.1912
    Database MEDical Literature Analysis and Retrieval System OnLINE

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