Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyomavirus middle T antigen (MT) is the major transforming protein of the virus. It functions through interactions with a number of cellular proteins involved in cell proliferation. MT forms complexes with protein phosphatase 2A (PP2A), pp60c-src, phosphatidylinositol 3-kinase, and Shc. We introduced both deletion and point mutations into three regions of MT and examined their ability to associate with PP2A and pp60c-src. The first 25 amino acid residues of MT are required for association with PP2A and pp60c-src. Amino acids 105 to 111, comprising the sequence Cys-Arg-Met-Pro-Leu-Thr-Cys, is also required for complex formation between MT and PP2A. However, the sequence Asp-Lys-Gly-Gly (amino acids 44 to 47), also found in the B subunit of PP2A, is dispensable for complex formation between MT and PP2A. We find a strict correlation between the ability of MT to associate with PP2A and the ability of MT to associate with pp60c-src. One mutant, L5E, associates with a phosphatase other than PP2A, pp60c-src, and phosphatidylinositol 3-kinase in a manner similar to that of wild-type MT yet is reduced in its transforming ability on NIH 3T3 cells.
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PMID:Amino-terminal regions of polyomavirus middle T antigen are required for interactions with protein phosphatase 2A. 753 75

Transformation of cells in culture by polyomavirus is mediated by one of its early gene products, middle-sized tumor antigen (MTAg). This protein forms multiple complexes with cellular enzymes such as tyrosine kinases (pp60c-src), a phosphatidylinositol 3-kinase, and phosphatase 2A. Association with MTAg leads to the activation of pp60c-src through interference with phosphorylation at Tyr-527, a site negatively regulating src kinase activity. MTAg abrogates mitosis-specific activation of pp60c-src, resulting in constitutive high kinase activity of the enzyme throughout all phases of the cell cycle. Here we report that MTAg is transiently modified during mitosis, resulting in an increase in its apparent molecular size on SDS/acrylamide gels. Similarly, MTAg isolated from interphase cells and phosphorylated by the cell cycle-regulated serine/threonine kinase p34cdc2 in vitro has increased molecular mass. The large molecular mass form of the protein can be converted to the authentic 56-kDa form upon dephosphorylation by potato acid phosphatase. Two putative phosphorylation sites for a cdc2-like kinase were identified as Thr-160 and -291, respectively. Conversion of Thr-160 to Ala resulted in a transformation-defective mutant protein that was still capable of associating with pp60c-src, phosphatidylinositol 3-kinase, and phosphatase 2A, while the corresponding mutant in position 291 was wild type with respect to all parameters measured so far. These data suggest that phosphorylation by p34cdc2 or a related cell cycle-regulated kinase modulates the interaction of MTAg with cellular targets that are crucial for cell transformation.
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PMID:Mitosis-specific phosphorylation of polyomavirus middle-sized tumor antigen and its role during cell transformation. 769 Jan 42

The mechanisms of action of the immunosuppressive drugs cyclosporin A (CsA), FK506 and rapamycin are strikingly conserved from yeast to human T cells. Recent results obtained with yeast corroborate calcineurin as the target of CsA-cyclophilin and FK506-FKBP complexes, and reveal a phosphatidylinositol 3-kinase homologue as the target of the rapamycin-FKBP complex.
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PMID:Cyclosporin A, FK506 and rapamycin: more than just immunosuppression. 769 98

The mechanisms by which cells rapidly polarize in the direction of external signals are not understood. Helper T cells, when contacted by an antigen-presenting cell, polarize their cytoskeletons toward the antigen-presenting cell within minutes. Here we show that, in T cells, the mammalian Ras-related GTPase CDC42 (the homologue of yeast CDC42, a protein involved in budding polarity) can regulate the polarization of both actin and microtubules toward antigen-presenting cells but is not involved in other T-cell signaling processes such as those which culminate in interleukin 2 production. Although T-cell polarization appears dispensable for signaling leading to interleukin 2 production, polarization may direct lymphokine secretion towards the correct antigen-presenting cell in a crowded cellular environment. Inhibitor experiments suggest that phosphatidylinositol 3-kinase is required for cytoskeletal polarization but that calcineurin activity, known to be important for other aspects of signaling, is not. Apparent conservation of CDC42 function between yeast and T cells suggests that this GTPase is a general regulator of cytoskeletal polarity in many cell types.
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PMID:Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. 776 42

Polyomavirus-infected cells express three proteins in the early phase of the lytic cycle, the so-called tumor antigens. Two of them, large- and middle-T antigens, are also required for virus-mediated transformation of primary cells, while middle-T alone is sufficient to transform established cells in culture. Cell transformation by middle-T is strictly dependent on the ability of this protein to associate with cellular enzymes like members of the Src family of tyrosine kinases, a phosphatidylinositol 3-kinase, phosphatase 2A and SHC, an adapter protein linking GDP/GTP exchange factors to tyrosine kinase receptors. A carboxy-terminal stretch of 22 hydrophobic amino acids is required for targeting middle-T and associated proteins to cellular membranes. Here we show in an in vitro system that middle-T fusion proteins carrying an amino-terminal hemagglutinin leader sequence are capable to bind to and enter the lumen of dog pancreas microsomes supporting the concept that the carboxy-terminus of middle-T is an authentic membrane-targeting domain. Furthermore, wild-type middle-T, but not a truncated protein lacking the putative membrane anchor, specifically associates with artificial lipid bilayers.
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PMID:Membrane association of polyomavirus middle-T antigen in an in vitro system. 776 90

Treatment of cells with okadaic acid, a protein phosphatase inhibitor, leads to an insulin-resistant state without modification in the tyrosine kinase activity of the receptor toward exogenous substrates. In 3T3-L1 adipocytes, okadaic acid induced a similar dose-dependent inhibition of the insulin effect on deoxyglucose uptake, phosphatidylinositol 3-kinase (PI 3-kinase) activation, and insulin receptor substrate (IRS) 1 tyrosine phosphorylation. Simultaneously, in okadaic acid-treated 3T3-L1 adipocytes, the reduced IRS 1 tyrosine phosphorylation was linked to a decrease in its electrophoretic mobility due to phosphorylation on serine/threonine residues. This phosphorylation appeared to result from the activation of cytosolic kinase(s). Furthermore, using in vitro reconstitution, we show that, compared to IRS 1 immunopurified from untreated cells, the IRS 1 obtained from okadaic acid-treated cells had a reduced capacity to be phosphorylated by insulin receptors and, concomitantly, to bind PI 3-kinase. Taken together these data suggest that serine/threonine phosphorylation of IRS 1 induced by okadaic acid reduces the ability of the insulin receptor to phosphorylate IRS 1 and to dock one of its interacting molecules, i.e. PI 3-kinase. Finally, the inhibitory effect of okadaic acid on the stimulatory action of insulin on glucose transport suggests that the serine/threonine phosphorylation of IRS 1 might represent a key regulatory mechanism of insulin action.
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PMID:Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. 811 50

Three proteins expressed early in the replicative cycle of polyomavirus also play an essential role during virus-mediated tumorigenesis. One of the proteins, middle-T antigen, has been shown to bind cellular proteins involved in cell signalling such as c-Src, phosphatase 2A, phosphatidylinositol 3-kinase and SHC. Association of middle-T antigen with cellular membranes has been shown to be essential for middle-T-mediated cell transformation. A mutant virus encoding a truncated form of middle-T lacking a carboxy-terminal hydrophobic sequence mediating membrane association is not oncogenic. This mutant middle-T still binds phosphatase 2A through amino-terminal sequences common to small-and middle-T and is localized in the nucleus, although the protein does not contain a classical nuclear targeting sequence. Mutations introduced into the amino-terminal domain affecting the ability of truncated middle-T to bind phosphatase 2A prevented accumulation of the protein in the nucleus and led to localization in the cytoplasm. This suggests that nuclear localization of truncated middle-T may be a consequence of binding to phosphatase 2A.
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PMID:Polyomavirus middle-T antigen lacking a membrane anchor sequence accumulates in the nucleus. 855 25

In this study, we examined the mechanism of recently reported inactivation of protein phosphatase-2A (PP-2A) by insulin (Srinivasan, M., and Begum, N. (1994) J. Biol. Chem. 269, 12514-12520) and its counter-regulation by cAMP agonists. Exposure of L6 myotubes to insulin resulted in a rapid inhibition of PP-2A that was accompanied by a 3-fold increase in the phosphotyrosine content of the immunoprecipitated PP-2A catalytic subunit. Pretreatment with (Sp)-cAMP, a cAMP agonist, completely blocked insulin-mediated inhibition of PP-2A activity and decreased the tyrosine phosphorylation of PP-2A catalytic subunit to control levels. To understand the mechanism of counter-regulation of PP-2A by (Sp)-cAMP, cells were pretreated with sodium orthovanadate, an inhibitor of phosphotyrosine phosphatases. Vanadate prevented the effect of (Sp)-cAMP on PP-2A activity and increased the phosphorylation status of PP-2A catalytic subunit to the level observed with insulin. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, an inhibitor of 70-kDa S6 kinase activation, prevented insulin-mediated inactivation of PP-2A, suggesting that these pathways may participate in insulin-mediated phosphorylation and inactivation of PP-2A. These results show that insulin signaling results in a rapid inactivation of PP-2A by increased tyrosine phosphorylation and cAMP agonists counter-regulate insulin's effect on PP-2A by decreasing phosphorylation, presumably via an activated phosphatase.
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PMID:cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells. 894 Jan 15

We have reported that inhibition of protein phosphatase 2A (PP2A) by expression of SV40 small t stimulates the mitogenic MAP kinase cascade. Here, we show that SV40 small t can substitute for tumor necrosis factor-alpha (TNF-alpha) or serum and stimulate atypical protein kinase C zeta (PKC zeta) activity, resulting in MEK activation, cell proliferation and NF-kappaB-dependent gene transcriptional activation in CV-1 and NIH 3T3 cells. These effects were abrogated by co-expression of kinase-deficient PKC zeta and inhibition of phosphatidylinositol 3-kinase p85alpha-p110 by wortmannin, LY294002 and a dominant-negative mutant of p85alpha. In contrast, expression of kinase-inactive ERK2 inhibited small t-dependent cell growth but was unable to abolish small t-induced NF-kappaB transactivation. Our results provide the first in vivo evidence for a critical regulatory role of PP2A in bifunctional PKC zeta signaling pathways controlled by phosphatidylinositol 3-kinase. Constitutive activation of PKC zeta and NF-kappaB following inhibition of PP2A supports new mechanisms by which SV40 small t promotes cell growth and transformation. By establishing PP2A as a key player in the response of cells to growth factors and stress signals like TNF-alpha, our findings could explain why PP2A is a primary target utilized during SV40 infection to alter cellular behavior.
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PMID:Protein phosphatase 2A is a critical regulator of protein kinase C zeta signaling targeted by SV40 small t to promote cell growth and NF-kappaB activation. 931 25

Glucose transport in mammalian skeletal muscle is stimulated by insulin, hypoxia and tyrosine protein phosphatase inhibitors such as vanadate. However, it is unknown whether the vanadate signaling mechanism shares a common or separate pathway with insulin or hypoxia. Therefore, experiments were conducted on incubated human muscle strips to compare the effects of vanadate with insulin and hypoxia stimulated 2-deoxyglucose transport (2-DOG). We also used the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin to examine whether PI 3-kinase is a common step by which each stimulate glucose transport. Results demonstrate that whereas the effects of vanadate and hypoxia were additive with insulin stimulated glucose transport, the effect of vanadate plus hypoxia was not. In addition, wortmannin significantly (P < 0.05) reduced insulin but not vanadate or hypoxia stimulated 2-DOG transport. Moreover, PI 3-kinase activity was significantly elevated (P < 0.05) in the presence of insulin but not vanadate. In conclusion, these data suggest that vanadate and hypoxia stimulate glucose transport via a similar signaling pathway which is distinct from insulin and that the vanadate signaling pathway is not mediated by PI 3-kinase in human skeletal muscle.
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PMID:Vanadate stimulation of 2-deoxyglucose transport is not mediated by PI 3-kinase in human skeletal muscle. 936 61


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