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  • 1
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    A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-02-12
    Description: Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boyce, Michael -- Bryant, Kevin F -- Jousse, Celine -- Long, Kai -- Harding, Heather P -- Scheuner, Donalyn -- Kaufman, Randal J -- Ma, Dawei -- Coen, Donald M -- Ron, David -- Yuan, Junying -- AI19838/AI/NIAID NIH HHS/ -- AI26077/AI/NIAID NIH HHS/ -- DDK42394/DK/NIDDK NIH HHS/ -- DK47119/DK/NIDDK NIH HHS/ -- ES08681/ES/NIEHS NIH HHS/ -- GM64703/GM/NIGMS NIH HHS/ -- NS35138/NS/NINDS NIH HHS/ -- R37-AG012859/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2005 Feb 11;307(5711):935-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15705855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Differentiation ; Apoptosis/*drug effects ; Cell Cycle Proteins ; Cell Line ; Cinnamates/*pharmacology/toxicity ; *Cytoprotection ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/*metabolism ; Enzyme Inhibitors/pharmacology ; Eukaryotic Initiation Factor-2/*metabolism ; Genes, Reporter ; Herpesvirus 1, Human/drug effects/physiology ; Keratitis, Herpetic/drug therapy/virology ; Male ; Mice ; Oxazoles/pharmacology/toxicity ; PC12 Cells ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Folding ; Protein Kinases/metabolism ; Protein Phosphatase 1 ; Proteins/metabolism ; Rats ; Thiourea/*analogs & derivatives/*pharmacology/toxicity ; Tunicamycin/pharmacology ; Viral Proteins/metabolism ; Virus Replication/drug effects
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-05-10
    Description: Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6). The proline-to-glutamine substitution at position 112, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II and appears to alter the intracellular distribution of TRPC6 protein. Previous work has emphasized the importance of cytoskeletal and structural proteins in proteinuric kidney diseases. Our findings suggest an alternative mechanism for the pathogenesis of glomerular disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winn, Michelle P -- Conlon, Peter J -- Lynn, Kelvin L -- Farrington, Merry Kay -- Creazzo, Tony -- Hawkins, April F -- Daskalakis, Nikki -- Kwan, Shu Ying -- Ebersviller, Seth -- Burchette, James L -- Pericak-Vance, Margaret A -- Howell, David N -- Vance, Jeffery M -- Rosenberg, Paul B -- R01 DK074748/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2005 Jun 17;308(5729):1801-4. Epub 2005 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. michelle.winn@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15879175" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Angiotensin II/metabolism/pharmacology ; Calcium/metabolism ; Calcium Channels/chemistry/*genetics/metabolism ; Calcium Signaling ; Carbachol/pharmacology ; Cell Line ; Cell Membrane/metabolism ; Chromosomes, Human, Pair 11/genetics ; Exons ; Female ; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; Glomerulosclerosis, Focal Segmental/*genetics ; Haplotypes ; Humans ; Kidney/metabolism ; Kidney Glomerulus/metabolism ; Kidney Tubules/metabolism ; Male ; *Mutation, Missense ; Patch-Clamp Techniques ; Pedigree ; Receptor, Angiotensin, Type 1/genetics/metabolism ; Sequence Analysis, DNA ; Sodium/metabolism ; TRPC Cation Channels ; Transfection ; Uridine Triphosphate/metabolism/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Mitogenic influence of human R-spondin1 on the intestinal epithelium (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-08-20
    Description: Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving beta-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Kyung-Ah -- Kakitani, Makoto -- Zhao, Jingsong -- Oshima, Takeshi -- Tang, Tom -- Binnerts, Minke -- Liu, Yi -- Boyle, Bryan -- Park, Emily -- Emtage, Peter -- Funk, Walter D -- Tomizuka, Kazuma -- New York, N.Y. -- Science. 2005 Aug 19;309(5738):1256-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nuvelo, Inc., 675 Almanor Avenue, Sunnyvale, CA 94085, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16109882" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/adverse effects ; Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; Chimera ; Colon/cytology/pathology ; Cytoskeletal Proteins/metabolism ; Dose-Response Relationship, Drug ; Enteroendocrine Cells/metabolism ; Epithelial Cells/metabolism ; Fibroblast Growth Factor 7 ; Fibroblast Growth Factors/pharmacology ; Fluorouracil/adverse effects ; Glucagon-Like Peptides ; Humans ; Intestinal Mucosa/*cytology/metabolism/pathology ; Intestine, Small/cytology/pathology ; Mice ; Mice, Transgenic ; *Mitogens ; Neoplasm Transplantation ; Neoplasms, Experimental/drug therapy/pathology ; Peptides/pharmacology ; Proteins/pharmacology ; Recombinant Proteins/pharmacology ; Thrombospondins/genetics/metabolism/pharmacology/*physiology ; Tongue/drug effects/pathology ; Trans-Activators/metabolism ; Wnt Proteins ; Wnt3 Protein ; beta Catenin
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-12-17
    Description: Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)-binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of poleta and poliota to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of poleta is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bienko, Marzena -- Green, Catherine M -- Crosetto, Nicola -- Rudolf, Fabian -- Zapart, Grzegorz -- Coull, Barry -- Kannouche, Patricia -- Wider, Gerhard -- Peter, Matthias -- Lehmann, Alan R -- Hofmann, Kay -- Dikic, Ivan -- New York, N.Y. -- Science. 2005 Dec 16;310(5755):1821-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16357261" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cell Line ; Computational Biology ; DNA/*biosynthesis ; *DNA Damage ; DNA Repair ; DNA Replication ; DNA-Directed DNA Polymerase/*chemistry/genetics/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Point Mutation ; Proliferating Cell Nuclear Antigen/metabolism ; Protein Binding ; Protein Conformation ; Protein Interaction Mapping ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/metabolism ; Transfection ; Ubiquitin/*metabolism ; Xeroderma Pigmentosum/genetics ; Zinc Fingers
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-08-27
    Description: CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Guangyong -- Guo, Zhong -- Kiniwa, Yukiko -- Voo, Kui Shin -- Peng, Weiyi -- Fu, Tihui -- Wang, Daniel Y -- Li, Yanchun -- Wang, Helen Y -- Wang, Rong-Fu -- P01CA94237/CA/NCI NIH HHS/ -- P50 CA093459/CA/NCI NIH HHS/ -- P50CA58204/CA/NCI NIH HHS/ -- R01CA101795/CA/NCI NIH HHS/ -- R01CA90327/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2005 Aug 26;309(5739):1380-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16123302" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Adoptive Transfer ; Animals ; Antigens, Differentiation/genetics/physiology ; CD4-Positive T-Lymphocytes/*immunology ; Cell Line ; Cell Line, Tumor ; Humans ; Immune Tolerance ; Interleukin-1 Receptor-Associated Kinases ; Killer Cells, Natural/immunology ; Ligands ; Lymphocyte Activation ; Membrane Glycoproteins/genetics/*physiology ; Mice ; Myeloid Differentiation Factor 88 ; Neoplasm Transplantation ; Neoplasms, Experimental/immunology/pathology ; Oligodeoxyribonucleotides/immunology ; Phosphotransferases (Alcohol Group Acceptor)/genetics/physiology ; Poly G/immunology ; RNA Interference ; Receptors, Cell Surface/genetics/*physiology ; Receptors, Immunologic/genetics/physiology ; *Signal Transduction ; T-Lymphocyte Subsets/*immunology ; Toll-Like Receptor 8 ; Toll-Like Receptors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-11-19
    Description: The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Millar, J Kirsty -- Pickard, Benjamin S -- Mackie, Shaun -- James, Rachel -- Christie, Sheila -- Buchanan, Sebastienne R -- Malloy, M Pat -- Chubb, Jennifer E -- Huston, Elaine -- Baillie, George S -- Thomson, Pippa A -- Hill, Elaine V -- Brandon, Nicholas J -- Rain, Jean-Christophe -- Camargo, L Miguel -- Whiting, Paul J -- Houslay, Miles D -- Blackwood, Douglas H R -- Muir, Walter J -- Porteous, David J -- G8604010/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2005 Nov 18;310(5751):1187-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. Kirsty.Millar@ed.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16293762" target="_blank"〉PubMed〈/a〉
    Keywords: 3',5'-Cyclic-AMP Phosphodiesterases/*genetics/metabolism ; Adult ; Affective Disorders, Psychotic/genetics/metabolism ; Animals ; Cadherins/genetics ; Cell Line ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 16 ; Cyclic AMP/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Enzyme Activation ; Genetic Predisposition to Disease ; Humans ; Male ; Nerve Tissue Proteins/*genetics/metabolism ; Protein Binding ; Rats ; Schizophrenia/enzymology/*genetics/metabolism ; *Signal Transduction ; Translocation, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Ethics: Moral issues of human-non-human primate neural grafting (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greene, Mark -- Schill, Kathryn -- Takahashi, Shoji -- Bateman-House, Alison -- Beauchamp, Tom -- Bok, Hilary -- Cheney, Dorothy -- Coyle, Joseph -- Deacon, Terrence -- Dennett, Daniel -- Donovan, Peter -- Flanagan, Owen -- Goldman, Steven -- Greely, Henry -- Martin, Lee -- Miller, Earl -- Mueller, Dawn -- Siegel, Andrew -- Solter, Davor -- Gearhart, John -- McKhann, Guy -- Faden, Ruth -- New York, N.Y. -- Science. 2005 Jul 15;309(5733):385-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Philosophy, University of Delaware, Newark, DE 19716, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16020716" target="_blank"〉PubMed〈/a〉
    Keywords: Advisory Committees ; Animal Experimentation/*ethics ; Animals ; Brain/anatomy & histology/physiology ; Cell Line ; *Ethics, Research ; Humans ; Mental Processes ; Moral Obligations ; *Morals ; Neurons/cytology/physiology/*transplantation ; *Primates/psychology ; Stem Cell Transplantation/*ethics ; Transplantation Chimera ; Transplantation, Heterologous/*ethics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Dependence of self-tolerance on TRAF6-directed development of thymic stroma (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-02-12
    Description: The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor-associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6(-/-) embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Akiyama, Taishin -- Maeda, Shiori -- Yamane, Sayaka -- Ogino, Kaori -- Kasai, Michiyuki -- Kajiura, Fumiko -- Matsumoto, Mitsuru -- Inoue, Jun-ichiro -- New York, N.Y. -- Science. 2005 Apr 8;308(5719):248-51. Epub 2005 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15705807" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity ; Cell Line ; Epithelial Cells/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Organ Culture Techniques ; Proto-Oncogene Proteins/physiology ; *Self Tolerance ; T-Lymphocytes/immunology ; TNF Receptor-Associated Factor 6/immunology/*physiology ; Thymus Gland/cytology/embryology/*immunology ; Transcription Factor RelB ; Transcription Factors/physiology
    Print ISSN: 0036-8075
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  • 9
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    PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-04-02
    Description: Activation of the transcription factor NF-kappaB after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C (PKC), the scaffold protein CARD11 (also called CARMA-1), the caspase recruitment domain (CARD)-containing protein Bcl10, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the IkappaB kinase (IKK) complex. However, the events proximal to the TCR that initiate the activation of this signaling pathway remain poorly defined. We demonstrate that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKC and through signal-dependent recruiting of both PKC and CARD11 to lipid rafts. PDK1-associated PKC recruits the IKK complex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1-dependent ubiquitination of the IKK complex subunit known as NEMO (NF-kappaB essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Ki-Young -- D'Acquisto, Fulvio -- Hayden, Matthew S -- Shim, Jae-Hyuck -- Ghosh, Sankar -- R37 AI033443/AI/NIAID NIH HHS/ -- R37-AI33443/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2005 Apr 1;308(5718):114-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15802604" target="_blank"〉PubMed〈/a〉
    Keywords: 3-Phosphoinositide-Dependent Protein Kinases ; Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis Regulatory Proteins ; CARD Signaling Adaptor Proteins ; Carrier Proteins/metabolism ; Caspases ; Cell Line ; Cell Line, Tumor ; Enzyme Activation ; Guanylate Cyclase/metabolism ; Humans ; I-kappa B Kinase ; Isoenzymes/genetics/*metabolism ; Jurkat Cells ; Lymphocyte Activation ; Lymphoma, B-Cell, Marginal Zone/metabolism ; Membrane Microdomains/metabolism ; Membrane Proteins/metabolism ; Models, Biological ; NF-kappa B/*metabolism ; Neoplasm Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Protein Kinase C/genetics/*metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; RNA Interference ; Receptors, Antigen, T-Cell/immunology/*metabolism ; *Signal Transduction ; T-Lymphocytes/enzymology/immunology/*metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-11-19
    Description: How cyclooxygenase-2 (COX-2) and its proinflammatory metabolite prostaglandin E2 (PGE2) enhance colon cancer progression remains poorly understood. We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Castellone, Maria Domenica -- Teramoto, Hidemi -- Williams, Bart O -- Druey, Kirk M -- Gutkind, J Silvio -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2005 Dec 2;310(5753):1504-10. Epub 2005 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16293724" target="_blank"〉PubMed〈/a〉
    Keywords: Axin Protein ; Cell Line ; Cell Proliferation ; Colonic Neoplasms/*pathology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Dinoprostone/*physiology ; GTP-Binding Protein alpha Subunits, Gs/*metabolism ; Genes, Reporter ; Humans ; RGS Proteins/metabolism ; Receptors, Prostaglandin E/metabolism ; Receptors, Prostaglandin E, EP2 Subtype ; Repressor Proteins/*metabolism ; *Signal Transduction ; beta Catenin/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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