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The three Type 2A protein phosphatases, PP2Ac, PP4c and PP6c, are differentially regulated by Alpha4.
LeNoue-Newton ML, Wadzinski BE, Spiller BW
(2016) Biochem Biophys Res Commun 475: 64-9
MeSH Terms: Catalytic Domain, Gene Knockdown Techniques, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Phosphoprotein Phosphatases, Protein Phosphatase 2
Show Abstract · Added March 15, 2018
Alpha4 is a non-canonical regulatory subunit of Type 2A protein phosphatases that interacts directly with the phosphatase catalytic subunits (PP2Ac, PP4c, and PP6c) and is upregulated in a variety of cancers. Alpha4 modulates phosphatase expression levels and activity, but the molecular mechanism of this regulation is unclear, and the extent to which the various Type 2A catalytic subunits associate with Alpha4 is also unknown. To determine the relative fractions of the Type 2A catalytic subunits associated with Alpha4, we conducted Alpha4 immunodepletion experiments in HEK293T cells and found that a significant fraction of total PP6c is associated with Alpha4, whereas a minimal fraction of total PP2Ac is associated with Alpha4. To facilitate studies of phosphatases in the presence of mutant or null Alpha4 alleles, we developed a facile and rapid method to simultaneously knockdown and rescue Alpha4 in tissue culture cells. This approach has the advantage that levels of endogenous Alpha4 are dramatically reduced by shRNA expression thereby simplifying interpretation of mutant phenotypes. We used this system to show that knockdown of Alpha4 preferentially impacts the expression of PP4c and PP6c compared to expression levels of PP2Ac.
Copyright © 2016. Published by Elsevier Inc.
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8 MeSH Terms
Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer.
Puvirajesinghe TM, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S, Sebbagh M, Lopez M, Brech A, Finetti P, Charafe-Jauffret E, Chaffanet M, Castellano R, Restouin A, Marchetto S, Collette Y, Gonçalvès A, Macara I, Birnbaum D, Kodjabachian L, Johansen T, Borg JP
(2016) Nat Commun 7: 10318
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Blotting, Western, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Cell Line, Tumor, Cell Migration Assays, Cell Movement, Cell Polarity, Cell Proliferation, DNA Copy Number Variations, Embryo, Nonmammalian, Female, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Mass Spectrometry, Membrane Proteins, Mice, Microscopy, Electron, Middle Aged, Neoplasm Transplantation, Prognosis, Proportional Hazards Models, RNA, Messenger, Sequestosome-1 Protein, Wnt Signaling Pathway, Xenopus
Show Abstract · Added April 10, 2018
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1-JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2-p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy.
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MeSH Terms
Personalizing Therapy in Idiopathic Pulmonary Fibrosis: A Glimpse of the Future?
Kropski JA, Lawson WE, Blackwell TS
(2015) Am J Respir Crit Care Med 192: 1409-11
MeSH Terms: Acetylcysteine, Female, Humans, Idiopathic Pulmonary Fibrosis, Intracellular Signaling Peptides and Proteins, Male, Mucin-5B
Added February 22, 2016
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7 MeSH Terms
Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver.
Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L, Sunny NE, He T, Nair LA, Livingston KA, Livingston K, Fu X, Merritt ME, Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ, Corbin I, Magnuson MA, Browning JD, Burgess SC
(2015) J Clin Invest 125: 4447-62
MeSH Terms: Animals, Hepatocytes, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Mice, Mitochondria, Liver, Non-alcoholic Fatty Liver Disease, Oxidative Stress, Phosphoenolpyruvate Carboxykinase (GTP), Rats, Rats, Wistar
Show Abstract · Added January 5, 2016
Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid-induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways.
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12 MeSH Terms
A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, Escarpe PA, Hampl J, Laysang A, Liu D, Lopez-Molina J, Milton M, Park A, Pysz MA, Shao H, Slingerland B, Torgov M, Williams SA, Foord O, Howard P, Jassem J, Badzio A, Czapiewski P, Harpole DH, Dowlati A, Massion PP, Travis WD, Pietanza MC, Poirier JT, Rudin CM, Stull RA, Dylla SJ
(2015) Sci Transl Med 7: 302ra136
MeSH Terms: Animals, Antibodies, Monoclonal, Antineoplastic Agents, Female, Humans, Immunoconjugates, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Membrane Proteins, Mice, Mice, Inbred NOD, Mice, SCID, Neuroendocrine Tumors, Xenograft Model Antitumor Assays
Show Abstract · Added February 16, 2016
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.
Copyright © 2015, American Association for the Advancement of Science.
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14 MeSH Terms
KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation.
Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T, Henderson JM, Bonventre JV
(2015) EMBO J 34: 2441-64
MeSH Terms: Antigen Presentation, Apoptosis, Autophagy-Related Protein 5, Autophagy-Related Protein-1 Homolog, CD4-Positive T-Lymphocytes, Cell Proliferation, HEK293 Cells, Hepatitis A Virus Cellular Receptor 1, Humans, Intracellular Signaling Peptides and Proteins, Lipoylation, Membrane Glycoproteins, Microtubule-Associated Proteins, Phagocytosis, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Receptors, Virus
Show Abstract · Added September 12, 2016
Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.
© 2015 The Authors.
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17 MeSH Terms
Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours.
Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, Baek J, Burdette L, Chang J, Chung C, Dawsey SM, Ding T, Gao YT, Giffen C, Han Y, Hong M, Huang J, Kim HS, Koh WP, Liao LM, Mao YM, Qiao YL, Shu XO, Tan W, Wang C, Wu C, Wu MJ, Xiang YB, Yeager M, Yook JH, Yuan JM, Zhang P, Zhao XK, Zheng W, Song K, Wang LD, Lin D, Chanock SJ, Goldstein AM, Taylor PR, Abnet CC
(2016) Gut 65: 1611-8
MeSH Terms: AMP-Activated Protein Kinases, Adenocarcinoma, Asian Continental Ancestry Group, Cardia, Case-Control Studies, China, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Male, Mucin-1, Polymorphism, Single Nucleotide, Republic of Korea, Stomach Neoplasms
Show Abstract · Added October 8, 2015
OBJECTIVE - Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia.
DESIGN - Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non-cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing.
RESULTS - We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36×10(-12)) and non-cardia cancers (p=2.42×10(-23)) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50×10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47×10(-2)). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59×10(-8) for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer.
CONCLUSIONS - Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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16 MeSH Terms
MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.
Evans BC, Hocking KM, Osgood MJ, Voskresensky I, Dmowska J, Kilchrist KV, Brophy CM, Duvall CL
(2015) Sci Transl Med 7: 291ra95
MeSH Terms: Animals, Endocytosis, Endosomes, Humans, Hyperplasia, Intracellular Signaling Peptides and Proteins, Lysosomes, Male, Myocytes, Smooth Muscle, Nanoparticles, Peptides, Phenotype, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Rabbits, Saphenous Vein, Treatment Outcome, Tunica Intima, Vascular Grafting
Show Abstract · Added March 14, 2018
Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.
Copyright © 2015, American Association for the Advancement of Science.
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20 MeSH Terms
Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection.
Callaway JB, Smith SA, McKinnon KP, de Silva AM, Crowe JE, Ting JP
(2015) J Biol Chem 290: 17306-20
MeSH Terms: Antibodies, Viral, Antibody-Dependent Enhancement, Antigen-Antibody Complex, Carrier Proteins, Caspase 1, Cells, Cultured, Dengue, Dengue Virus, Glyburide, Humans, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Monocytes, NLR Family, Pyrin Domain-Containing 3 Protein, Protein-Tyrosine Kinases, RNA, Messenger, RNA, Small Interfering, Syk Kinase, Virus Replication
Show Abstract · Added January 26, 2016
Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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20 MeSH Terms
A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.
Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D
(2015) PLoS One 10: e0125482
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, Cisplatin, DNA Repair, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Drug Synergism, Gene Library, HCT116 Cells, Humans, Intracellular Signaling Peptides and Proteins, Pyrazines, RNA, Small Interfering, Sulfones, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added February 4, 2016
The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.
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18 MeSH Terms