Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 11 to 20 of 53

Publication Record

Connections

The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress.
Yan L, Guo S, Brault M, Harmon J, Robertson RP, Hamid R, Stein R, Yang E
(2012) Biochem J 444: 239-47
MeSH Terms: Amino Acid Sequence, Animals, Cells, Cultured, Forkhead Box Protein O1, Forkhead Transcription Factors, HEK293 Cells, Humans, Insulin-Secreting Cells, Islets of Langerhans, Isoenzymes, Mice, Mice, Transgenic, Molecular Sequence Data, Oxidative Stress, Phosphorylation, Protein Phosphatase 2, Rats, Up-Regulation
Show Abstract · Added March 7, 2014
The FOXO1 (forkhead box O1) transcription factor influences many key cellular processes, including those important in metabolism, proliferation and cell death. Reversible phosphorylation of FOXO1 at Thr(24) and Ser(256) regulates its subcellular localization, with phosphorylation promoting cytoplasmic localization, whereas dephosphorylation triggers nuclear import and transcriptional activation. In the present study, we used biochemical and molecular approaches to isolate and link the serine/threonine PP2A (protein phosphatase 2A) holoenzyme containing the B55α regulatory subunit, with nuclear import of FOXO1 in pancreatic islet β-cells under oxidative stress, a condition associated with cellular dysfunction in Type 2 diabetes. The mechanism of FOXO1 dephosphorylation and nuclear translocation was investigated in pancreatic islet INS-1 and βTC-3 cell lines subjected to oxidative stress. A combined chemical cross-linking and MS strategy revealed the association of FOXO1 with a PP2A holoenzyme composed of the catalytic C, structural A and B55α regulatory subunits. Knockdown of B55α in INS-1 cells reduced FOXO1 dephosphorylation, inhibited FOXO1 nuclear translocation and attenuated oxidative stress-induced cell death. Furthermore, both B55α and nuclear FOXO1 levels were increased under hyperglycaemic conditions in db/db mouse islets, an animal model of type 2 diabetes. We conclude that B55α-containing PP2A is a key regulator of FOXO1 activity in vivo.
0 Communities
2 Members
0 Resources
18 MeSH Terms
The E3 ubiquitin ligase- and protein phosphatase 2A (PP2A)-binding domains of the Alpha4 protein are both required for Alpha4 to inhibit PP2A degradation.
LeNoue-Newton M, Watkins GR, Zou P, Germane KL, McCorvey LR, Wadzinski BE, Spiller BW
(2011) J Biol Chem 286: 17665-71
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Animals, Binding Sites, Crystallography, X-Ray, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Mice, Molecular Chaperones, Phosphoproteins, Protein Phosphatase 2, Protein Structure, Tertiary, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added March 7, 2014
Protein phosphatase 2A (PP2A) is regulated through a variety of mechanisms, including post-translational modifications and association with regulatory proteins. Alpha4 is one such regulatory protein that binds the PP2A catalytic subunit (PP2Ac) and protects it from polyubiquitination and degradation. Alpha4 is a multidomain protein with a C-terminal domain that binds Mid1, a putative E3 ubiquitin ligase, and an N-terminal domain containing the PP2Ac-binding site. In this work, we present the structure of the N-terminal domain of mammalian Alpha4 determined by x-ray crystallography and use double electron-electron resonance spectroscopy to show that it is a flexible tetratricopeptide repeat-like protein. Structurally, Alpha4 differs from its yeast homolog, Tap42, in two important ways: 1) the position of the helix containing the PP2Ac-binding residues is in a more open conformation, showing flexibility in this region; and 2) Alpha4 contains a ubiquitin-interacting motif. The effects of wild-type and mutant Alpha4 on PP2Ac ubiquitination and stability were examined in mammalian cells by performing tandem ubiquitin-binding entity precipitations and cycloheximide chase experiments. Our results reveal that both the C-terminal Mid1-binding domain and the PP2Ac-binding determinants are required for Alpha4-mediated protection of PP2Ac from polyubiquitination and degradation.
© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
2 Members
0 Resources
17 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, Cell Cycle Proteins, 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.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis.
Widau RC, Jin Y, Dixon SA, Wadzinski BE, Gallagher PJ
(2010) J Biol Chem 285: 13827-38
MeSH Terms: Amino Acid Substitution, Anoikis, Apoptosis Regulatory Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Ceramides, Cytoskeleton, Death-Associated Protein Kinases, HeLa Cells, Holoenzymes, Humans, Mutation, Missense, Phosphorylation, Protein Phosphatase 2, Tumor Suppressor Proteins
Show Abstract · Added March 26, 2014
The tumor suppressor, death-associated protein kinase (DAPK), is a Ca(2+)/calmodulin-regulated Ser/Thr kinase with an important role in regulating cytoskeletal dynamics. Autophosphorylation within the calmodulin-binding domain at Ser-308 inhibits DAPK catalytic activity. Dephosphorylation of Ser-308 by a previously unknown phosphatase enhances kinase activity and proteasome-mediated degradation of DAPK. In these studies, we identified two holoenzyme forms of protein phosphatase 2A (PP2A), ABalphaC and ABdeltaC, as DAPK-interacting proteins. These phosphatase holoenzymes dephosphorylate DAPK at Ser-308 in vitro and in vivo resulting in enhanced kinase activity of DAPK. The enzymatic activity of PP2A also negatively regulates DAPK levels by enhancing proteasome-mediated degradation of the kinase. Overexpression of wild type DAPK induces cell rounding and detachment in HEK293 cells; however, this effect is not observed following expression of an inactive DAPK S308E mutant. Finally, activation of DAPK by PP2A was found to be required for ceramide-induced anoikis. Together, our results provide a mechanism by which PP2A and DAPK activities control cell adhesion and anoikis.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination.
McConnell JL, Watkins GR, Soss SE, Franz HS, McCorvey LR, Spiller BW, Chazin WJ, Wadzinski BE
(2010) Biochemistry 49: 1713-8
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Blotting, Western, Cell Line, Electrophoresis, Polyacrylamide Gel, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Spectroscopy, Microtubule Proteins, Models, Biological, Molecular Chaperones, Nuclear Proteins, Protein Binding, Protein Phosphatase 2, Transcription Factors, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added December 5, 2013
Multiple regulatory mechanisms control the activity of the protein serine/threonine phosphatase 2A catalytic subunit (PP2Ac), including post-translational modifications and its association with regulatory subunits and interacting proteins. Alpha4 is a PP2Ac-interacting protein that is hypothesized to play a role in PP2Ac ubiquitination via its interaction with the E3 ubiquitin ligase Mid1. In this report, we show that alpha4 serves as a necessary adaptor protein that provides a binding platform for both PP2Ac and Mid1. We also identify a novel ubiquitin-interacting motif (UIM) within alpha4 (amino acid residues 46-60) and analyze the interaction between alpha4 and ubiquitin using NMR. Consistent with other UIM-containing proteins, alpha4 is monoubiquitinated. Interestingly, deletion of the UIM within alpha4 enhances its association with polyubiquitinated proteins. Lastly, we demonstrate that addition of wild-type alpha4 but not an alpha4 UIM deletion mutant suppresses PP2Ac polyubiquitination. Thus, the polyubiquitination of PP2Ac is inhibited by the UIM within alpha4. These findings reveal direct regulation of PP2Ac polyubiquitination by a novel UIM within the adaptor protein alpha4.
1 Communities
3 Members
0 Resources
19 MeSH Terms
Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk.
Dupont WD, Breyer JP, Bradley KM, Schuyler PA, Plummer WD, Sanders ME, Page DL, Smith JR
(2010) Cancer 116: 8-19
MeSH Terms: Adult, Breast Diseases, Breast Neoplasms, Female, Genes, Tumor Suppressor, Haplotypes, Humans, Middle Aged, Polymorphism, Single Nucleotide, Precancerous Conditions, Protein Phosphatase 2, Retrospective Studies, Risk Assessment
Show Abstract · Added March 5, 2014
BACKGROUND - Protein phosphatase 2A (PP2A) is a major cellular phosphatase and plays key regulatory roles in growth, differentiation, and apoptosis. Women who are diagnosed with benign proliferative breast disease are at increased risk for the subsequent development of breast cancer.
METHODS - The authors evaluated genetic variation of PP2A holoenzyme subunits for their potential contribution to breast cancer risk. A nested case-control investigation was performed on a cohort of women who had a history of benign breast disease. The women were followed for an average of 18 years, and DNA prepared from the original archival benign breast biopsy (1954-1995) was available for 450 women who were diagnosed with breast cancer on follow-up and for 890 of 900 women in a control group who were matched on race, age, and year of entry biopsy.
RESULTS - Single allele-based and haplotype-based tests of association were conducted with assessment of significance by permutation testing. Significant risk and protective haplotypes of the PP2A structural/regulatory subunit A alpha isoform (PPP2R1A) were identified and had odds ratios of 1.63 (95% confidence interval [CI], 1.3-2.1) and 0.55 (95% CI, 0.41-0.76), respectively. These odds ratios remained significant after the analysis was adjusted for multiple comparisons. Women who had both the PPP2R1A risk haplotype and a history of proliferative breast disease had an odds ratio of 2.44 (95% CI, 1.7-3.5) for the subsequent development of breast cancer. The effects of haplotypes for 2 PP2A regulatory subunit genes, PP2 regulatory subunit B alpha isoform (PPP2R2A) and PP2A regulatory subunit B' epsilon isoform (PPP2R5E) on breast cancer risk were nominally significant but did not remain significant after the analysis was adjusted for multiple comparisons.
CONCLUSIONS - The current findings supported the previously hypothesized role of PP2A as a tumor suppressor gene in breast cancer.
Copyright 2010 American Cancer Society.
0 Communities
3 Members
0 Resources
13 MeSH Terms
The Balpha and Bdelta regulatory subunits of PP2A are necessary for assembly of the CaMKIV.PP2A signaling complex.
Reece KM, Mazalouskas MD, Wadzinski BE
(2009) Biochem Biophys Res Commun 386: 582-7
MeSH Terms: Antibodies, Phospho-Specific, Calcium-Calmodulin-Dependent Protein Kinase Type 4, Cell Line, Holoenzymes, Humans, Mutation, Phosphorylation, Protein Phosphatase 2, Protein Subunits, Signal Transduction
Show Abstract · Added March 26, 2014
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a serine/threonine kinase that is important in synaptic plasticity and T cell maturation. Activation of CaMKIV requires calcium/calmodulin binding and phosphorylation at T200 by CaMK kinase. Our previous work has shown that protein serine/threonine phosphatase 2A (PP2A) forms a complex with CaMKIV and negatively regulates its activity. Here we demonstrate that PP2A tightly regulates T200 phosphorylation of endogenous CaMKIV, but has little effect on the phosphorylation of the ectopically-expressed kinase. This differential regulation of endogenous versus exogenous CaMKIV is due to differences in their ability to associate with PP2A, as exogenous CaMKIV associates poorly with PP2A in comparison to endogenous CaMKIV. The inability of exogenous CaMKIV to associate with PP2A appears to be due to limiting amounts of endogenous PP2A regulatory B subunits, since coexpression of Balpha or Bdelta causes the recruitment of PP2Ac to ectopic CaMKIV, leading to formation of a CaMKIV.PP2A complex. Together, these data indicate that the B subunits are essential for the interaction of PP2A with CaMKIV.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Thyroid hormone effects on LKB1, MO25, phospho-AMPK, phospho-CREB, and PGC-1alpha in rat muscle.
Branvold DJ, Allred DR, Beckstead DJ, Kim HJ, Fillmore N, Condon BM, Brown JD, Sudweeks SN, Thomson DM, Winder WW
(2008) J Appl Physiol (1985) 105: 1218-27
MeSH Terms: AMP-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Antithyroid Agents, Blotting, Western, Calcium-Binding Proteins, Cyclic AMP Response Element-Binding Protein, Disease Models, Animal, Electric Stimulation, Hyperthyroidism, Hypothyroidism, Male, Mitochondrial Proteins, Multienzyme Complexes, Muscle, Skeletal, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphoprotein Phosphatases, Phosphorylation, Promoter Regions, Genetic, Propylthiouracil, Protein Phosphatase 2C, Protein-Serine-Threonine Kinases, RNA, Messenger, RNA-Binding Proteins, Rats, Rats, Sprague-Dawley, Signal Transduction, Thyroxine, Transcription Factors, Triiodothyronine
Show Abstract · Added October 23, 2017
Expression of all of the isoforms of the subunits of AMP-activated protein kinase (AMPK) and AMPK activity is increased in skeletal muscle of hyperthyroid rats. Activity of AMPK in skeletal muscle is regulated principally by the upstream kinase, LKB1. This experiment was designed to determine whether the increase in AMPK activity is accompanied by increased expression of the LKB1, along with binding partner proteins. LKB1, MO25, and downstream targets were determined in muscle extracts in control rats, in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 4 wk, and in rats given 0.01% propylthiouracil (PTU; an inhibitor of thyroid hormone synthesis) in drinking water for 4 wk (hypothyroid group). LKB1 and MO25 increased in the soleus of thyroid hormone-treated rats vs. the controls. In other muscle types, LKB1 responses were variable, but MO25 increased in all. In soleus, MO25 mRNA increased with thyroid hormone treatment, and STRAD mRNA increased with PTU treatment. Phospho-AMPK and phospho-ACC were elevated in soleus and gastrocnemius of hyperthyroid rats. Thyroid hormone treatment also increased the amount of phospho-cAMP response element binding protein (CREB) in the soleus, heart, and red quadriceps. Four proteins having CREB response elements (CRE) in promoter regions of their genes (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, uncoupling protein 3, cytochrome c, and hexokinase II) were all increased in soleus in response to thyroid hormones. These data provide evidence that thyroid hormones increase soleus muscle LKB1 and MO25 content with subsequent activation of AMPK, phosphorylation of CREB, and expression of mitochondrial protein genes having CRE in their promoters.
0 Communities
1 Members
0 Resources
31 MeSH Terms
Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans.
Carneiro AM, Cook EH, Murphy DL, Blakely RD
(2008) J Clin Invest 118: 1544-52
MeSH Terms: Alleles, Animals, Biological Transport, Blood Platelets, Cell Line, Cell Membrane, Humans, MAP Kinase Signaling System, Mice, Mice, Knockout, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Binding, Protein Phosphatase 1, Protein Phosphatase 2, Serotonin, Serotonin Plasma Membrane Transport Proteins, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 10, 2013
The essential contribution of the antidepressant-sensitive serotonin (5-HT) transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores suggests an important role of this transporter in platelet function. Here, using SERT-deficient mice, we have established a role for constitutive SERT expression in efficient ADP- and thrombin-triggered platelet aggregation. Additionally, using pharmacological blockers of SERT and the vesicular monoamine transporter (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in efficient human platelet aggregation. We have also demonstrated that fibrinogen, an activator of integrin alphaIIbbeta3, enhances SERT activity in human platelets and that integrin alphaIIbbeta3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin beta3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin beta3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of alphaIIbbeta3/SERT associations as well as alphaIIbbeta3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.
1 Communities
2 Members
0 Resources
18 MeSH Terms
Role of protein phosphatase 2A in regulating the visual signaling in Drosophila.
Wang N, Leung HT, Pak WL, Carl YT, Wadzinski BE, Shieh BH
(2008) J Neurosci 28: 1444-51
MeSH Terms: Action Potentials, Adaptation, Ocular, Amino Acid Sequence, Animals, Catalysis, Drosophila, Drosophila Proteins, Eye Proteins, Female, Male, Molecular Sequence Data, Phosphorylation, Photoreceptor Cells, Invertebrate, Protein Phosphatase 2, Signal Transduction, Visual Perception
Show Abstract · Added December 10, 2013
Drosophila visual signaling, a G-protein-coupled phospholipase Cbeta (PLCbeta)-mediated mechanism, is regulated by eye-protein kinase C (PKC) that promotes light adaptation and fast deactivation, most likely via phosphorylation of inactivation no afterpotential D (INAD) and TRP (transient receptor potential). To reveal the critical phosphatases that dephosphorylate INAD, we used several biochemical analyses and identified protein phosphatase 2A (PP2A) as a candidate. Importantly, the catalytic subunit of PP2A, microtubule star (MTS), is copurified with INAD, and an elevated phosphorylation of INAD by eye-PKC was observed in three mts heterozygotes. To explore whether PP2A (MTS) regulates dephosphorylation of INAD by counteracting eye-PKC [INAC (inactivation no afterpotential C] in vivo, we performed ERG recordings. We discovered that inaC(P209) was semidominant, because inaC(P209) heterozygotes displayed abnormal light adaptation and slow deactivation. Interestingly, the deactivation defect of inaC(P209) heterozygotes was rescued by the mts(XE2258) heterozygous background. In contrast, mts(XE2258) failed to modify the severe deactivation of norpA(P16), indicating that MTS does not modulate NORPA (no receptor potential A) (PLCbeta). Together, our results strongly indicate that dephosphorylation of INAD is catalyzed by PP2A, and a reduction of PP2A can compensate for a partial loss of function in eye-PKC, restoring the fast deactivation kinetics in vivo. We thus propose that the fast deactivation of the visual response is modulated in part by the phosphorylation of INAD.
0 Communities
1 Members
0 Resources
16 MeSH Terms