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Ubiquitin turnover and endocytic trafficking in yeast are regulated by Ser57 phosphorylation of ubiquitin.
Lee S, Tumolo JM, Ehlinger AC, Jernigan KK, Qualls-Histed SJ, Hsu PC, McDonald WH, Chazin WJ, MacGurn JA
(2017) Elife 6:
MeSH Terms: Endocytosis, Homeostasis, Phosphoprotein Phosphatases, Phosphorylation, Protein Processing, Post-Translational, Saccharomyces cerevisiae Proteins, Ubiquitin, Yeasts
Show Abstract · Added March 24, 2018
Despite its central role in protein degradation little is known about the molecular mechanisms that sense, maintain, and regulate steady state concentration of ubiquitin in the cell. Here, we describe a novel mechanism for regulation of ubiquitin homeostasis that is mediated by phosphorylation of ubiquitin at the Ser57 position. We find that loss of Ppz phosphatase activity leads to defects in ubiquitin homeostasis that are at least partially attributable to elevated levels of Ser57 phosphorylated ubiquitin. Phosphomimetic mutation at the Ser57 position of ubiquitin conferred increased rates of endocytic trafficking and ubiquitin turnover. These phenotypes are associated with bypass of recognition by endosome-localized deubiquitylases - including Doa4 which is critical for regulation of ubiquitin recycling. Thus, ubiquitin homeostasis is significantly impacted by the rate of ubiquitin flux through the endocytic pathway and by signaling pathways that converge on ubiquitin itself to determine whether it is recycled or degraded in the vacuole.
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8 MeSH Terms
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
Greatwall-phosphorylated Endosulfine is both an inhibitor and a substrate of PP2A-B55 heterotrimers.
Williams BC, Filter JJ, Blake-Hodek KA, Wadzinski BE, Fuda NJ, Shalloway D, Goldberg ML
(2014) Elife 3: e01695
MeSH Terms: Cell Cycle, Drosophila Proteins, Gene Expression Regulation, Enzymologic, Peptides, Phosphoprotein Phosphatases, Phosphorylation, Protein-Serine-Threonine Kinases
Show Abstract · Added March 26, 2014
During M phase, Endosulfine (Endos) family proteins are phosphorylated by Greatwall kinase (Gwl), and the resultant pEndos inhibits the phosphatase PP2A-B55, which would otherwise prematurely reverse many CDK-driven phosphorylations. We show here that PP2A-B55 is the enzyme responsible for dephosphorylating pEndos during M phase exit. The kinetic parameters for PP2A-B55's action on pEndos are orders of magnitude lower than those for CDK-phosphorylated substrates, suggesting a simple model for PP2A-B55 regulation that we call inhibition by unfair competition. As the name suggests, during M phase PP2A-B55's attention is diverted to pEndos, which binds much more avidly and is dephosphorylated more slowly than other substrates. When Gwl is inactivated during the M phase-to-interphase transition, the dynamic balance changes: pEndos dephosphorylated by PP2A-B55 cannot be replaced, so the phosphatase can refocus its attention on CDK-phosphorylated substrates. This mechanism explains simultaneously how PP2A-B55 and Gwl together regulate pEndos, and how pEndos controls PP2A-B55. DOI: http://dx.doi.org/10.7554/eLife.01695.001.
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7 MeSH Terms
Protein phosphatase 2A family members (PP2A and PP6) associate with U1 snRNP and the spliceosome during pre-mRNA splicing.
Kamoun M, Filali M, Murray MV, Awasthi S, Wadzinski BE
(2013) Biochem Biophys Res Commun 440: 306-11
MeSH Terms: HEK293 Cells, HeLa Cells, Humans, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 2, RNA Splicing, Ribonucleoprotein, U1 Small Nuclear, Ribonucleoprotein, U2 Small Nuclear, Spliceosomes, Thymocytes
Show Abstract · Added March 7, 2014
Protein phosphorylation and dephosphorylation are both important for multiple steps in the splicing pathway. Members of the PP1 and PP2A subfamilies of phospho-serine/threonine phosphatases play essential but redundant roles in the second step of the splicing reaction. PP6, a member of the PP2A subfamily, is the mammalian homolog of yeast Sit4p and ppe1, which are involved in cell cycle regulation; however, the involvement of PP6 in the splicing pathway remains unclear. Here we show that PP2A family members physically associate with the spliceosome throughout the splicing reaction. PP2A holoenzyme and PP6 were found stably associated with U1 snRNP. Together our findings indicate that these phosphatases regulate splicing catalysis involving U1 snRNP and suggest an important evolutionary conserved role of PP2A family phosphatases in pre-mRNA splicing.
Copyright © 2013 Elsevier Inc. All rights reserved.
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11 MeSH Terms
PPM1A is a RelA phosphatase with tumor suppressor-like activity.
Lu X, An H, Jin R, Zou M, Guo Y, Su PF, Liu D, Shyr Y, Yarbrough WG
(2014) Oncogene 33: 2918-27
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Cell Nucleus, Chemokine CCL2, Disease Models, Animal, Gene Expression, Heterografts, Humans, Male, Mice, NF-kappa B, Neoplasm Metastasis, Phosphoprotein Phosphatases, Phosphorylation, Prostatic Neoplasms, Protein Binding, Protein Phosphatase 2C, Protein Transport, Transcription Factor RelA, Transcription, Genetic, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins
Show Abstract · Added March 10, 2014
Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.
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23 MeSH Terms
Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent.
Palmer ND, Musani SK, Yerges-Armstrong LM, Feitosa MF, Bielak LF, Hernaez R, Kahali B, Carr JJ, Harris TB, Jhun MA, Kardia SL, Langefeld CD, Mosley TH, Norris JM, Smith AV, Taylor HA, Wagenknecht LE, Liu J, Borecki IB, Peyser PA, Speliotes EK
(2013) Hepatology 58: 966-75
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, African Continental Ancestry Group, Aged, Chondroitin Sulfate Proteoglycans, Cohort Studies, European Continental Ancestry Group, Fatty Liver, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Hispanic Americans, Humans, Lectins, C-Type, Lipase, Lysophospholipase, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Non-alcoholic Fatty Liver Disease, Phosphoprotein Phosphatases
Show Abstract · Added February 28, 2014
UNLABELLED - Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African- and/or Hispanic-Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age(2) , gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m(2) , respectively. Hepatic steatosis was 0.20-0.34 heritable in African- and Hispanic-American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
CONCLUSION - Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African- and Hispanic-Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
© 2013 by the American Association for the Study of Liver Diseases.
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23 MeSH Terms
Essential roles of the Tap42-regulated protein phosphatase 2A (PP2A) family in wing imaginal disc development of Drosophila melanogaster.
Wang N, Leung HT, Mazalouskas MD, Watkins GR, Gomez RJ, Wadzinski BE
(2012) PLoS One 7: e38569
MeSH Terms: Animals, Apoptosis, Drosophila Proteins, Drosophila melanogaster, Imaginal Discs, Immunohistochemistry, Morphogenesis, Phosphoprotein Phosphatases, RNA Interference, Signal Transduction, Transcription Factors, Wings, Animal
Show Abstract · Added March 7, 2014
Protein ser/thr phosphatase 2A family members (PP2A, PP4, and PP6) are implicated in the control of numerous biological processes, but our understanding of the in vivo function and regulation of these enzymes is limited. In this study, we investigated the role of Tap42, a common regulatory subunit for all three PP2A family members, in the development of Drosophila melanogaster wing imaginal discs. RNAi-mediated silencing of Tap42 using the binary Gal4/UAS system and two disc drivers, pnr- and ap-Gal4, not only decreased survival rates but also hampered the development of wing discs, resulting in a remarkable thorax cleft and defective wings in adults. Silencing of Tap42 also altered multiple signaling pathways (HH, JNK and DPP) and triggered apoptosis in wing imaginal discs. The Tap42(RNAi)-induced defects were the direct result of loss of regulation of Drosophila PP2A family members (MTS, PP4, and PPV), as enforced expression of wild type Tap42, but not a phosphatase binding defective Tap42 mutant, rescued fly survivorship and defects. The experimental platform described herein identifies crucial roles for Tap42•phosphatase complexes in governing imaginal disc and fly development.
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12 MeSH Terms
LZAP inhibits p38 MAPK (p38) phosphorylation and activity by facilitating p38 association with the wild-type p53 induced phosphatase 1 (WIP1).
An H, Lu X, Liu D, Yarbrough WG
(2011) PLoS One 6: e16427
MeSH Terms: Cell Compartmentation, Humans, Intracellular Signaling Peptides and Proteins, Nerve Tissue Proteins, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Protein Phosphatase 2C, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added June 27, 2013
LZAP (Cdk5rap3, C53) is a putative tumor suppressor that inhibits RelA, Chk1 and Chk2 and activates p53. LZAP is lost in a portion of human head and neck squamous cell carcinoma and experimental loss of LZAP expression is associated with enhanced invasion, xenograft tumor growth and angiogenesis. p38 MAPK can increase or decrease proliferation and cell death depending on cellular context. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by its protein-protein interactions. To gain further insight into LZAP activities, we searched for LZAP-associated proteins (LAPs). Here we show that the LZAP binds p38, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. Expression of LZAP inhibits p38 phosphorylation in a dose-dependent fashion while loss of LZAP enhances phosphorylation and activation with resultant phosphorylation of p38 downstream targets. Mechanistically, the ability of LZAP to alter p38 phosphorylation depended, at least partially, on the p38 phosphatase, Wip1. Expression of LZAP increased both LZAP and Wip1 binding to p38. Taken together, these data suggest that LZAP activity includes inhibition of p38 phosphorylation and activation.
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11 MeSH Terms
B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression.
Irish JM, Myklebust JH, Alizadeh AA, Houot R, Sharman JP, Czerwinski DK, Nolan GP, Levy R
(2010) Proc Natl Acad Sci U S A 107: 12747-54
MeSH Terms: B-Lymphocytes, CD40 Antigens, Disease Progression, Enzyme Activation, Extracellular Space, Humans, Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, Lymphoma, Follicular, Models, Immunological, Phenotype, Phosphoprotein Phosphatases, Prognosis, Receptors, Antigen, B-Cell, Reproducibility of Results, Signal Transduction, Survival Analysis
Show Abstract · Added February 15, 2013
Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient's disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell-cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.
1 Communities
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17 MeSH Terms
A link between aurora kinase and Clp1/Cdc14 regulation uncovered by the identification of a fission yeast borealin-like protein.
Bohnert KA, Chen JS, Clifford DM, Vander Kooi CW, Gould KL
(2009) Mol Biol Cell 20: 3646-59
MeSH Terms: Amino Acid Sequence, Aurora Kinases, Cell Cycle Proteins, Chromosomes, Fungal, Cytokinesis, Humans, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Phosphoprotein Phosphatases, Protein Structure, Secondary, Protein Subunits, Protein Tyrosine Phosphatases, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 5, 2014
The chromosomal passenger complex (CPC) regulates various events in cell division. This complex is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin. Together, these four subunits interdependently regulate CPC function, and they are highly conserved among eukaryotes. However, a Borealin homologue has never been characterized in the fission yeast, Schizosaccharomyces pombe. Here, we isolate a previously uncharacterized S. pombe protein through association with the Cdc14 phosphatase homologue, Clp1/Flp1, and identify it as a Borealin-like member of the CPC. Nbl1 (novel Borealin-like 1) physically associates with known CPC components, affects the kinase activity and stability of the S. pombe Aurora B homologue, Ark1, colocalizes with known CPC subunits during mitosis, and shows sequence similarity to human Borealin. Further analysis of the Clp1-Nbl1 interaction indicates that Clp1 requires CPC activity for proper accumulation at the contractile ring (CR). Consistent with this, we describe negative genetic interactions between mutant alleles of CPC and CR components. Thus, this study characterizes a fission yeast Borealin homologue and reveals a previously unrecognized connection between the CPC and the process of cytokinesis in S. pombe.
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17 MeSH Terms