The Experts below are selected from a list of 33693 Experts worldwide ranked by ideXlab platform
Jenny P Y Ting - One of the best experts on this subject based on the ideXlab platform.
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inflammasome associated nucleotide binding domain leucine rich Repeat proteins and inflammatory diseases
Journal of Immunology, 2009Co-Authors: Sushmita Jha, Jenny P Y TingAbstract:The nucleotide-binding domain, Leucine-Rich Repeat (NLR) proteins are a recently discovered family of intracellular pathogen and danger signal sensors. NLRs have emerged as important contributors to innate immunity in animals. The physiological impact of these genes is increasingly evident, underscored by the genetic association of variant family members with an array of inflammatory diseases. The association of mutations in NLR genes with autoinflammatory diseases indicates an important function of these genes in inflammation in vivo. This review summarizes the role of the inflammasome NLR proteins in innate immunity and inflammatory diseases and explores the possible utility of some of these NLRs as pharmacological targets.
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nlr the nucleotide binding domain leucine rich Repeat containing gene family
Current Opinion in Immunology, 2008Co-Authors: Jenny P Y TingAbstract:The NLR (nucleotide-binding domain Leucine-Rich Repeat containing) family is found in plants and animals, and serves as crucial regulators of inflammatory and innate immune response, though its functions are likely to extend greatly beyond innate immunity, and even beyond the immune system. This review discusses recent findings regarding the function of NLR proteins in the control of IL-1, NF-κB, and host response to pathogens including distinct forms of cell death. The review also covers recent advances regarding the biochemical nature of NLRs, its regulation by intracellular nucleotides and extracellular ATP, by the chaperone protein HSP90, and the ubiquitin ligase-associated protein SGT1. Its role in inflammation is linked to the formation of biochemical complexes such as the inflammasome, and its roles in cell death might be linked to the proposed formation of pyroptosome and necrosome.
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cutting edge monarch 1 a pyrin nucleotide binding domain leucine rich Repeat protein that controls classical and nonclassical mhc class i genes
Journal of Immunology, 2003Co-Authors: Kristi L Williams, Debra J Taxman, Michael W Linhoff, William Reed, Jenny P Y TingAbstract:Proteins containing a limited number of N-terminal motifs followed by nucleotide-binding domain and Leucine-Rich Repeat regions are emerging as important regulators for immunity. A search of human genome scaffold databases has identified a large family of known and unknown genes, which we have recently called the CATERPILLER (caspase recruitment domain, transcription enhancer, r(purine)-binding, pyrin, lots of leucine Repeats) gene family. This work describes the characterization of a new member, Monarch-1. Monarch-1 has four different splice forms due to the differential splicing of Leucine-Rich Repeat motifs. It is expressed in cells of myeloid-monocytic origin. Affymetrix microarrays and small interfering RNA were used to elucidate the downstream effects of Monarch-1 expression in cells including those of myeloid-monocytic origin. These analyses show that Monarch-1 enhances nonclassical and classical MHC class I expression at the level of the promoter, RNA, and protein expression.
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two distinct domains within ciita mediate self association involvement of the gtp binding and leucine rich Repeat domains
Molecular and Cellular Biology, 2001Co-Authors: Michael W Linhoff, Jonathan A Harton, Drew E Cressman, Brian K Martin, Jenny P Y TingAbstract:CIITA is the master regulator of class II major histocompatibility complex gene expression. We present evidence that CIITA can self-associate via two domains: the C terminus (amino acids 700 to 1130) and the GTP-binding domain (amino acids 336 to 702). Heterotypic and homotypic interactions are observed between these two regions. Deletions within the GTP-binding domain that reduce GTP-binding and transactivation function also reduce self-association. In addition, two leucine residues in the C-terminal Leucine-Rich Repeat region are critical for self-association as well as function. This study reveals for the first time a complex pattern of CIITA self-association. These interactions are discussed with regard to the apoptosis signaling proteins, Apaf-1 and Nod1, which share domain arrangements similar to those of CIITA.
Alexandra C. Newton - One of the best experts on this subject based on the ideXlab platform.
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Pleckstrin homology domain Leucine-Rich Repeat protein phosphatase (PHLPP): a new player in cell signaling.
The Journal of biological chemistry, 2011Co-Authors: Noel A. Warfel, Alexandra C. NewtonAbstract:Precise balance between phosphorylation, catalyzed by protein kinases, and dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states that drive diseases such as cancer, heart disease, and diabetes. The recent discovery of the PHLPP (pleckstrin homology domain Leucine-Rich Repeat protein phosphatase) family of Ser/Thr phosphatases adds a new player to the cast of phosphate-controlling enzymes in cell signaling. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis. The frequent deletion of PHLPP in cancer, coupled with the development of prostate tumors in mice lacking PHLPP1, identifies PHLPP as a novel tumor suppressor. This minireview discusses the structure, function, and regulation of PHLPP, with particular focus on its role in disease.
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discovery of small molecule inhibitors of the ph domain leucine rich Repeat protein phosphatase phlpp by chemical and virtual screening
Journal of Medicinal Chemistry, 2010Co-Authors: Emma Sierecki, William Sinko, Andrew J Mccammon, Alexandra C. NewtonAbstract:PH domain Leucine-Rich Repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways. Here we report on the discovery of small molecule inhibitors of the phosphatase activity of PHLPP, a member of the PP2C family of phosphatases for which there are no general pharmacological inhibitors. First, the Diversity Set of the NCI was screened for inhibition of the purified phosphatase domain of PHLPP2 in vitro. Second, selected libraries from the open NCI database were docked into a virtual model of the phosphatase domain of PHLPP2, previously trained with our experimental data set, unveiling additional inhibitors. Biochemical and cellular assays resulted in the identification of two structurally diverse compounds that selectively inhibit PHLPP in vitro, increase Akt signaling in cells, and prevent apoptosis. Thus, chemical and virtual screening has resulted in the identification o...
Emma Sierecki - One of the best experts on this subject based on the ideXlab platform.
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pleckstrin homology domain leucine rich Repeat protein phosphatases set the amplitude of receptor tyrosine kinase output
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Gloria Reyes, Matt Niederst, Ksenya Cohenkatsenelson, Joshua D Stender, Maya T Kunkel, Muhan Chen, John Brognard, Emma Sierecki, Tianyan Gao, Dawid G NowakAbstract:Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain Leucine-Rich Repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs.
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discovery of small molecule inhibitors of the ph domain leucine rich Repeat protein phosphatase phlpp by chemical and virtual screening
Journal of Medicinal Chemistry, 2010Co-Authors: Emma Sierecki, William Sinko, Andrew J Mccammon, Alexandra C. NewtonAbstract:PH domain Leucine-Rich Repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways. Here we report on the discovery of small molecule inhibitors of the phosphatase activity of PHLPP, a member of the PP2C family of phosphatases for which there are no general pharmacological inhibitors. First, the Diversity Set of the NCI was screened for inhibition of the purified phosphatase domain of PHLPP2 in vitro. Second, selected libraries from the open NCI database were docked into a virtual model of the phosphatase domain of PHLPP2, previously trained with our experimental data set, unveiling additional inhibitors. Biochemical and cellular assays resulted in the identification of two structurally diverse compounds that selectively inhibit PHLPP in vitro, increase Akt signaling in cells, and prevent apoptosis. Thus, chemical and virtual screening has resulted in the identification o...
Dawid G Nowak - One of the best experts on this subject based on the ideXlab platform.
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pleckstrin homology domain leucine rich Repeat protein phosphatases set the amplitude of receptor tyrosine kinase output
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Gloria Reyes, Matt Niederst, Ksenya Cohenkatsenelson, Joshua D Stender, Maya T Kunkel, Muhan Chen, John Brognard, Emma Sierecki, Tianyan Gao, Dawid G NowakAbstract:Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain Leucine-Rich Repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs.
Noel A. Warfel - One of the best experts on this subject based on the ideXlab platform.
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Pleckstrin homology domain Leucine-Rich Repeat protein phosphatase (PHLPP): a new player in cell signaling.
The Journal of biological chemistry, 2011Co-Authors: Noel A. Warfel, Alexandra C. NewtonAbstract:Precise balance between phosphorylation, catalyzed by protein kinases, and dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states that drive diseases such as cancer, heart disease, and diabetes. The recent discovery of the PHLPP (pleckstrin homology domain Leucine-Rich Repeat protein phosphatase) family of Ser/Thr phosphatases adds a new player to the cast of phosphate-controlling enzymes in cell signaling. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis. The frequent deletion of PHLPP in cancer, coupled with the development of prostate tumors in mice lacking PHLPP1, identifies PHLPP as a novel tumor suppressor. This minireview discusses the structure, function, and regulation of PHLPP, with particular focus on its role in disease.