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Franz X Schmid - One of the best experts on this subject based on the ideXlab platform.
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Cooperation of the Prolyl Isomerase and chaperone activities of the protein folding catalyst SlyD.
Journal of molecular biology, 2010Co-Authors: Gabriel Zoldák, Franz X SchmidAbstract:The SlyD (sensitive to lysis D) protein of Escherichia coli is a folding enzyme with a chaperone domain and a Prolyl Isomerase domain of the FK506 binding protein type. Here we investigated how the two domains and their interplay are optimized for function in protein folding. Unfolded protein molecules initially form a highly dynamic complex with the chaperone domain of SlyD, and they are then transferred to the Prolyl Isomerase domain. The turnover number of the Prolyl Isomerase site is very high and guarantees that, after transfer, Prolyl peptide bonds in substrate proteins are isomerized very rapidly. The Michaelis constant of catalyzed folding reflects the substrate affinity of the chaperone domain, and the turnover number is presumably determined by the rate of productive substrate transfer from the chaperone to the Prolyl Isomerase site and by the intrinsic propensity of the refolding protein chain to leave the active site with the native Prolyl isomer. The efficiency of substrate transfer is high because dissociation from the chaperone site is very fast and because the two sites are close to each other. Protein molecules that left the Prolyl Isomerase site with an incorrect Prolyl isomer can rapidly be re-bound by the chaperone domain because the association rate is very high as well.
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NMR Solution Structure of SlyD from Escherichia coli: Spatial Separation of Prolyl Isomerase and Chaperone Function
Journal of molecular biology, 2009Co-Authors: Ulrich Weininger, Gabriel Zoldák, Christian Scholz, Peter Schaarschmidt, Caroline Haupt, Kristian Schweimer, Wenke Graubner, Michael Kovermann, Thomas Brüser, Franz X SchmidAbstract:Summary SlyD (sensitive to lysis D) is a putative folding helper from the bacterial cytosol and harbors Prolyl Isomerase and chaperone activities. We determined the solution NMR structure of a truncated version of SlyD (1–165) from Escherichia coli (SlyD ⁎ ) that lacks the presumably unstructured C-terminal tail. SlyD ⁎ consists of two well-separated domains: the FKBP domain, which harbors the Prolyl Isomerase activity, and the insert-in-flap (IF) domain, which harbors the chaperone activity. The IF domain is inserted into a loop of the FKBP domain near the Prolyl Isomerase active site. The NMR structure of SlyD ⁎ showed no distinct orientation of the two domains relative to each other. In the FKBP domain, Tyr68 points into the active site, which might explain the lowered intrinsic Prolyl Isomerase activity and the much lower FK506 binding affinity of the protein compared with archetype human FKBP12 (human FK506 binding protein with 12 kDa). The thermodynamics and kinetics of substrate binding by SlyD ⁎ were quantified by fluorescence resonance energy transfer. NMR titration experiments revealed that the IF domain recognizes and binds unfolded or partially folded proteins and peptides. Insulin aggregation is markedly slowed by SlyD ⁎ as evidenced by two-dimensional NMR spectroscopy in real time, probably due to SlyD ⁎ binding to denatured insulin. The capacity of the IF domain to establish an initial encounter–collision complex, together with the flexible orientation of the two interacting domains, makes SlyD ⁎ a very powerful catalyst of protein folding.
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SlyD proteins from different species exhibit high Prolyl Isomerase and chaperone activities
Biokhimiia (Moscow Russia), 2006Co-Authors: Christian Scholz, Barbara Eckert, Franz Hagn, Peter Schaarschmidt, Jochen Balbach, Franz X SchmidAbstract:SlyD is a putative folding helper protein from the Escherichia coli cytosol, which consists of an N-terminal Prolyl Isomerase domain of the FKBP type and a presumably unstructured C-terminal tail. ...
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R73A and H144Q mutants of the yeast mitochondrial cyclophilin Cpr3 exhibit a low Prolyl Isomerase activity in both peptide and protein-folding assays.
FEBS letters, 1999Co-Authors: Christian Scholz, Kara Dolinski, Joseph Heitman, Peter Maier, Franz X SchmidAbstract:Previously we reported that the R73A and H144Q variants of the yeast cyclophilin Cpr3 were virtually inactive in a protease-coupled peptide assay, but retained activity as catalysts of a proline-limited protein folding reaction [Scholz, C. et al. (1997) FEBS Lett. 414, 69–73]. A reinvestigation revealed that in fact these two mutations strongly decrease the Prolyl Isomerase activity of Cpr3 in both the peptide and the protein-folding assay. The high folding activities found previously originated from a contamination of the recombinant Cpr3 proteins with the Escherichia coli protein SlyD, a Prolyl Isomerase that co-purifies with His-tagged proteins. SlyD is inactive in the peptide assay, but highly active in the protein-folding assay.
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Recognition of protein substrates by the Prolyl Isomerase trigger factor is independent of proline residues.
Journal of molecular biology, 1998Co-Authors: Christian Scholz, Matthias Mücke, Michael Rape, Anja Pecht, Andreas Pahl, Holger Bang, Franz X SchmidAbstract:The trigger factor is associated with bacterial ribosomes and catalyzes proline-limited protein folding reactions. Its folding activity is very high and conserved in evolution, as shown for the homologous enzymes from Escherichia coli and Mycoplasma genitalium. The folding protein substrate (a variant of ribonuclease T1) binds with high affinity to the trigger factors, and permanently unfolded proteins are strong, competitive inhibitors. We used this inhibition to characterize the substrate binding sites of the trigger factors. Unfolded α-lactalbumin binds very tightly and inhibits the trigger factor from M. genitalium with a KI value of 50 nM. The binding of inhibitory proteins is independent of proline residues, as shown for unfolded tendamistat, which binds to the trigger factor with equal affinity in the presence and in the absence of its three proline residues. The good inhibition by a non-folding variant of ribonuclease T1 that lacks Pro39 showed that this proline, at which the catalysis of folding occurs, is dispensable for substrate binding. The trigger factors cannot catalyze Prolyl isomerization when proteins are partially folded already. They preferentially recognize unstructured protein chains, which bind with high affinity to a site distinct from the catalytic Prolyl Isomerase center in the FKBP domain.
Xiao Zhen Zhou - One of the best experts on this subject based on the ideXlab platform.
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Prolyl Isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4
Oncogene, 2017Co-Authors: Shi-hui Dong, Jinjing Chen, Xiao Zhen Zhou, Ruichuan Chen, Satish K. Nair, Lin Feng ChenAbstract:Prolyl Isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4
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Prolyl Isomerase pin1 regulates axon guidance by stabilizing crmp2a selectively in distal axons
Cell Reports, 2015Co-Authors: Martin Balastik, Xiao Zhen Zhou, Meritxell Alberichjorda, Romana Weissova, Jakub žiak, Maria F Pazyramurphy, Katharina E Cosker, Olga Machonova, Iryna Kozmikova, Chunhau ChenAbstract:Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the Prolyl Isomerase Pin1. We demonstrate that Pin1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, Pin1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by Pin1 or CRMP2A expression. Moreover, Pin1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover Pin1-catalyzed Prolyl isomerization as a regulatory mechanism in axon guidance.
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Theileria parasites secrete a Prolyl Isomerase to maintain host leukocyte transformation
Nature, 2015Co-Authors: Justine Marsolier, Xiao Zhen Zhou, Martine Perichon, Jeremy D. Debarry, Bruno O. Villoutreix, Johanna Chluba, Tatiana Lopez, Carmen Garrido, Lauriane FritschAbstract:Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-Prolyl Isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide Prolyl Isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.
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Death-Associated Protein Kinase 1 Phosphorylates Pin1 and Inhibits Its Prolyl Isomerase Activity and Cellular Function
Molecular cell, 2011Co-Authors: Tae Ho Lee, Chunhau Chen, Futoshi Suizu, Pengyu Huang, Cordelia Schiene-fischer, Sebastian Daum, Yan Jessie Zhang, Alison Goate, Ruey-hwa Chen, Xiao Zhen ZhouAbstract:Pin1 is a phospho-specific Prolyl Isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since Prolyl Isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function.
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The Prolyl Isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease
Nature reviews. Molecular cell biology, 2007Co-Authors: Xiao Zhen ZhouAbstract:Phosphorylation is a universal regulatory mechanism that induces changes in protein conformation. However, certain phosphorylated motifs can be further regulated by the Prolyl Isomerase PIN1, which is of increasing importance in aspects of physiology and disease. Protein phosphorylation regulates many cellular processes by causing changes in protein conformation. The Prolyl Isomerase PIN1 has been identified as a regulator of phosphorylation signalling that catalyses the conversion of specific phosphorylated motifs between the two completely distinct conformations in a subset of proteins. PIN1 regulates diverse cellular processes, including growth-signal responses, cell-cycle progression, cellular stress responses, neuronal function and immune responses. In line with the diverse physiological roles of PIN1, it has also been linked to several diseases that include cancer, Alzheimer's disease and asthma, and thus it might represent a novel therapeutic target.
Christian Scholz - One of the best experts on this subject based on the ideXlab platform.
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NMR Solution Structure of SlyD from Escherichia coli: Spatial Separation of Prolyl Isomerase and Chaperone Function
Journal of molecular biology, 2009Co-Authors: Ulrich Weininger, Gabriel Zoldák, Christian Scholz, Peter Schaarschmidt, Caroline Haupt, Kristian Schweimer, Wenke Graubner, Michael Kovermann, Thomas Brüser, Franz X SchmidAbstract:Summary SlyD (sensitive to lysis D) is a putative folding helper from the bacterial cytosol and harbors Prolyl Isomerase and chaperone activities. We determined the solution NMR structure of a truncated version of SlyD (1–165) from Escherichia coli (SlyD ⁎ ) that lacks the presumably unstructured C-terminal tail. SlyD ⁎ consists of two well-separated domains: the FKBP domain, which harbors the Prolyl Isomerase activity, and the insert-in-flap (IF) domain, which harbors the chaperone activity. The IF domain is inserted into a loop of the FKBP domain near the Prolyl Isomerase active site. The NMR structure of SlyD ⁎ showed no distinct orientation of the two domains relative to each other. In the FKBP domain, Tyr68 points into the active site, which might explain the lowered intrinsic Prolyl Isomerase activity and the much lower FK506 binding affinity of the protein compared with archetype human FKBP12 (human FK506 binding protein with 12 kDa). The thermodynamics and kinetics of substrate binding by SlyD ⁎ were quantified by fluorescence resonance energy transfer. NMR titration experiments revealed that the IF domain recognizes and binds unfolded or partially folded proteins and peptides. Insulin aggregation is markedly slowed by SlyD ⁎ as evidenced by two-dimensional NMR spectroscopy in real time, probably due to SlyD ⁎ binding to denatured insulin. The capacity of the IF domain to establish an initial encounter–collision complex, together with the flexible orientation of the two interacting domains, makes SlyD ⁎ a very powerful catalyst of protein folding.
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SlyD proteins from different species exhibit high Prolyl Isomerase and chaperone activities
Biokhimiia (Moscow Russia), 2006Co-Authors: Christian Scholz, Barbara Eckert, Franz Hagn, Peter Schaarschmidt, Jochen Balbach, Franz X SchmidAbstract:SlyD is a putative folding helper protein from the Escherichia coli cytosol, which consists of an N-terminal Prolyl Isomerase domain of the FKBP type and a presumably unstructured C-terminal tail. ...
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R73A and H144Q mutants of the yeast mitochondrial cyclophilin Cpr3 exhibit a low Prolyl Isomerase activity in both peptide and protein-folding assays.
FEBS letters, 1999Co-Authors: Christian Scholz, Kara Dolinski, Joseph Heitman, Peter Maier, Franz X SchmidAbstract:Previously we reported that the R73A and H144Q variants of the yeast cyclophilin Cpr3 were virtually inactive in a protease-coupled peptide assay, but retained activity as catalysts of a proline-limited protein folding reaction [Scholz, C. et al. (1997) FEBS Lett. 414, 69–73]. A reinvestigation revealed that in fact these two mutations strongly decrease the Prolyl Isomerase activity of Cpr3 in both the peptide and the protein-folding assay. The high folding activities found previously originated from a contamination of the recombinant Cpr3 proteins with the Escherichia coli protein SlyD, a Prolyl Isomerase that co-purifies with His-tagged proteins. SlyD is inactive in the peptide assay, but highly active in the protein-folding assay.
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Recognition of protein substrates by the Prolyl Isomerase trigger factor is independent of proline residues.
Journal of molecular biology, 1998Co-Authors: Christian Scholz, Matthias Mücke, Michael Rape, Anja Pecht, Andreas Pahl, Holger Bang, Franz X SchmidAbstract:The trigger factor is associated with bacterial ribosomes and catalyzes proline-limited protein folding reactions. Its folding activity is very high and conserved in evolution, as shown for the homologous enzymes from Escherichia coli and Mycoplasma genitalium. The folding protein substrate (a variant of ribonuclease T1) binds with high affinity to the trigger factors, and permanently unfolded proteins are strong, competitive inhibitors. We used this inhibition to characterize the substrate binding sites of the trigger factors. Unfolded α-lactalbumin binds very tightly and inhibits the trigger factor from M. genitalium with a KI value of 50 nM. The binding of inhibitory proteins is independent of proline residues, as shown for unfolded tendamistat, which binds to the trigger factor with equal affinity in the presence and in the absence of its three proline residues. The good inhibition by a non-folding variant of ribonuclease T1 that lacks Pro39 showed that this proline, at which the catalysis of folding occurs, is dispensable for substrate binding. The trigger factors cannot catalyze Prolyl isomerization when proteins are partially folded already. They preferentially recognize unstructured protein chains, which bind with high affinity to a site distinct from the catalytic Prolyl Isomerase center in the FKBP domain.
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Cyclophilin active site mutants have native Prolyl Isomerase activity with a protein substrate
FEBS letters, 1997Co-Authors: Christian Scholz, Thomas Schindler, Kara Dolinski, Joseph Heitman, Franz X SchmidAbstract:The Prolyl Isomerase activity of cyclophilins is traditionally measured by an assay in which Prolyl cis/trans isomerization in a chromogenic tetrapeptide is coupled with its isomer-specific cleavage by chymotrypsin. Two variants of mitochondrial cyclophilin with substitutions in the presumed active site (R73A and H144Q) are inactive in the protease-coupled assay, but show almost wild-type activity in an assay that is based on the catalysis of a proline-limited protein folding reaction. This Prolyl Isomerase assay is preferable, both because coupling with proteolysis is avoided and because an intact protein instead of a short peptide is used as a substrate. Possibly, some earlier conclusions about the catalytic mechanism and the involvement of the Prolyl Isomerase activity in the cellular function of immunophilins may need reevaluation.
James S. Malter - One of the best experts on this subject based on the ideXlab platform.
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tlr 7 stress signaling in differentiating and mature eosinophils is mediated by the Prolyl Isomerase pin1
Journal of Immunology, 2018Co-Authors: Zhong Jian Shen, Venkatesh P Kashi, Yury A Bochkov, James E Gern, James S. MalterAbstract:The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the Prolyl Isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild-type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection.
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Phosphate-Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1.
PloS one, 2016Co-Authors: Zhong Jian Shen, Kazuhiro Shiizaki, Makoto Kuro-o, James S. MalterAbstract:Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-Prolyl Isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8–12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process.
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mixed lineage kinase 3 phosphorylates Prolyl Isomerase pin1 to regulate its nuclear translocation and cellular function
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Velusamy Rangasamy, James S. Malter, Tae Ho Lee, Rajakishore Mishra, Gautam Sondarva, Subhasis Das, Joanna C Bakowska, Guri Tzivion, Basabi Rana, Anumantha G KanthasamyAbstract:Nuclear protein peptidyl-Prolyl Isomerase Pin1-mediated Prolyl isomerization is an essential and novel regulatory mechanism for protein phosphorylation. Therefore, tight regulation of Pin1 localization and catalytic activity is crucial for its normal nuclear functions. Pin1 is commonly dysregulated during oncogenesis and likely contributes to these pathologies; however, the mechanism(s) by which Pin1 catalytic activity and nuclear localization are increased is unknown. Here we demonstrate that mixed-lineage kinase 3 (MLK3), a MAP3K family member, phosphorylates Pin1 on a Ser138 site to increase its catalytic activity and nuclear translocation. This phosphorylation event drives the cell cycle and promotes cyclin D1 stability and centrosome amplification. Notably, Pin1 pSer138 is significantly up-regulated in breast tumors and is localized in the nucleus. These findings collectively suggest that the MLK3-Pin1 signaling cascade plays a critical role in regulating the cell cycle, centrosome numbers, and oncogenesis.
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The peptidyl-Prolyl Isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation
Nature Immunology, 2009Co-Authors: Zhong Jian Shen, Stephane Esnault, Anna C. Schinzel, Christoph Borner, James S. MalterAbstract:The mechanisms through which cytokine signals prevent the activation and mitochondrial targeting of the pro-apoptotic Bcl-2-associated X protein (Bax) are unclear. Here we showed, using primary human eosinophils, that in the absence of the pro-survival cytokines granulocyte macrophage-colony stimulating factor (GM-CSF) or interleukin 5, Bax spontaneously undergoes activation and initiates mitochondrial disruption. Bax inhibition reduced eosinophil apoptosis, even in the absence of cytokines. GM-CSF induced activation of Erk1/2, which phosphorylated Thr167 of Bax, which facilitated de novo interaction of Bax with the Prolyl Isomerase Pin1. Pin1 blockade led to Bax cleavage, mitochondrial translocation and caspase activation, irrespective of the presence of cytokines. Our findings indicate that Pin1 is a key mediator of pro-survival signaling and a regulator of Bax function.
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pinning down signaling in the immune system the role of the peptidyl Prolyl Isomerase pin1 in immune cell function
Critical Reviews in Immunology, 2008Co-Authors: Stephane Esnault, Zong Jian Shen, James S. MalterAbstract:The peptidyl Prolyl Isomerase (PPIase) Pin1 has been recently implicated in cell cycle control and neuropathologies. There is now growing evidence that Pin1 plays an important role in the immune system and does so differentially from the related PPIases, cyclophilinA and FKBP. This review describes how Pin1 modulates cytokine expression by activated T cells and eosinophils and participates in T-cell and eosinophil apoptotic decisions both in vitro and in vivo. We highlight several possible immunologic diseases, including asthma, as well as organ transplant rejection, where anti-Pin1 therapeutics may be of value.
Greg Finn - One of the best experts on this subject based on the ideXlab platform.
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negative regulation of the stability and tumor suppressor function of fbw7 by the pin1 Prolyl Isomerase
Molecular Cell, 2012Co-Authors: Sang Hyun Min, Greg Finn, Tae Ho Lee, Pengyu Huang, Alan W Lau, Hiroyuki Inuzuka, Shuo Wei, Shavali Shaik, Daniel Yenhong Lee, Martin BalastikAbstract:Fbw7 is the substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex and a well-characterized tumor suppressor that targets numerous oncoproteins for destruction. Genomic deletion or mutation of FBW7 has been frequently found in various types of human cancers; however, little is known about the upstream signaling pathway(s) governing Fbw7 stability and cellular functions. Here we report that Fbw7 protein destruction and tumor suppressor function are negatively regulated by the Prolyl Isomerase Pin1. Pin1 interacts with Fbw7 in a phoshorylation-dependent manner and promotes Fbw7 self-ubiquitination and protein degradation by disrupting Fbw7 dimerization. Consequently, overexpressing Pin1 reduces Fbw7 abundance and suppresses Fbw7's ability to inhibit proliferation and transformation. By contrast, depletion of Pin1 in cancer cells leads to elevated Fbw7 expression, which subsequently reduces Mcl-1 abundance, sensitizing cancer cells to Taxol. Thus, Pin1-mediated inhibition of Fbw7 contributes to oncogenesis, and Pin1 may be a promising drug target for anticancer therapy.
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phosphorylation specific Prolyl Isomerase pin1 as a new diagnostic and therapeutic target for cancer
Current Cancer Drug Targets, 2008Co-Authors: Greg FinnAbstract:Proline directed phosphorylation is a key regulatory mechanism controlling the function of fundamental proteins involved in cell proliferation and oncogenic transformation. Recently, the identification of the phosphorylation dependent Prolyl Isomerase Pin1 has uncovered a distinct regulatory mechanism controlling protein function. Specifically, Pin1 controls the conversion of peptidyl proline bond conversion from cis to trans, only when the preceding serine or threonine is phosphorylated. The intrinsic inter-conversion of such bonds is rather slow and is further inhibited by phosphorylation. As a consequence catalysis by Pin1 is required to overcome this restriction. Importantly, structural evidence has now demonstrated that Pin1-catalyzed Prolyl isomerization can have significant effects on the global structure of substrate proteins. Furthermore, Pin1 overexpression is found in several types of cancer where it functions to not only promote tumorigenesis induced by oncogenes such as Ras and Neu, but also to regulate molecules that facilitate persistent proliferative capacity. Consequently, Pin1-mediated phosphorylation-dependent isomerization represents a unique regulatory mechanism in cell signaling whose deregulation during tumorigenesis adds to the pro-proliferative capacity of tumor cells and therefore Pin1 represents a novel tumor marker and potential therapeutic target.
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Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the Prolyl Isomerase Pin1
Nature Immunology, 2006Co-Authors: Tatsuya Saitoh, Greg Finn, Kun Ping Lu, Naoki Yamamoto, Shizuo Akira, Masahiro Yamamoto, Takashi Fujita, Shoji YamaokaAbstract:Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)–dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-Prolyl Isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-β, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.
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negative regulation of interferon regulatory factor 3 dependent innate antiviral response by the Prolyl Isomerase pin1
Nature Immunology, 2006Co-Authors: Tatsuya Saitoh, Greg Finn, Naoki Yamamoto, Shizuo Akira, Masahiro Yamamoto, Takashi Fujita, Akihide Ryo, Adrian Tunkyi, Shoji YamaokaAbstract:Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-Prolyl Isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.
