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)

Bax is a major proapoptotic member of the Bcl2 family that is required for apoptotic cell death. We have recently discovered that Bax phosphorylation at serine 184 induced by nicotine through activation of protein kinase AKT abolishes its proapoptotic function in human lung cancer cells. Here we found that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor okadaic acid or specific disruption of PP2A activity by expression of SV40 small tumor antigen enhanced Bax phosphorylation, whereas C(2)-ceramide, a potent PP2A activator, reduced nicotine-induced Bax phosphorylation, suggesting that PP2A may function as a physiological Bax phosphatase. PP2A co-localized and interacted with Bax. Purified, active PP2A directly dephosphorylated Bax in vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppressed nicotine-stimulated Bax phosphorylation in association with increased apoptotic cell death. By contrast, depletion of PP2A/C by RNA interference enhanced Bax phosphorylation and prolonged cell survival. Mechanistically C(2)-ceramide-induced Bax dephosphorylation caused a conformational change by exposure of the 6A7 epitope (amino acids 13-19) that is normally hidden at its N terminus that promoted the insertion of Bax into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis. In addition, PP2A directly disrupted the Bcl2/Bax association to liberate Bax from the heterodimer complex. Thus, PP2A may function as a physiological Bax regulatory phosphatase that not only dephosphorylates Bax but also activates its proapoptotic function.
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PMID:Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. 1667 23

The PTEN protein has a single catalytic domain possessing both lipid phosphoinositol and protein phosphatase activities. The lipid phosphoinositol phosphatase activity is essential for PTEN to block the cell cycle in the G1 phase and thereby to suppress tumor formation and progression (Cantley, L. C., and Neel, B. G. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 4240-4245), although the mechanisms governing PTEN activity under normal and neoplastic growth conditions remain unclear. Here, we report that PTEN interacts physically and functionally with PCAF, a histone acetyltransferase that regulates gene transcription through interaction with p300/CBP and various sequence-specific transcription factors (Nakatani, Y. (2001) Genes Cells 6, 79-86). Expression of PCAF results in increased acetylation of lysine residues (Lys125 and Lys128) within the catalytic cleft of PTEN, a structure essential for phosphatidylinositol 3,4,5-trisphosphate specificity (Lee, J. O., Yang, H., Georgescu, M. M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J. E., Pandolfi, P., and Pavletich, N. P. (1999) Cell 99, 323-334). The acetylation of PTEN caused by PCAF expression depends on the presence of growth factors. Reduction of endogenous PCAF activity using shRNA results in a loss of PTEN acetylation in response to growth factors and restores the ability of PTEN to down-regulate phosphatidylinositol 3-kinase signaling and to induce G1 cell cycle arrest. The retention of phosphatidylinositol 3-kinase/AKT signaling and cell cycle regulatory activities of acetylation-resistant PTEN K125R and K128R mutants in the presence of enforced PCAF expression suggest a causal relationship. Together, these findings indicate a mechanism of PTEN regulation that forges a link between distinct cancer-relevant pathways central to the control of growth factor signaling and gene expression.
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PMID:PCAF modulates PTEN activity. 1682 19

Protein kinase B (PKB), an Ag receptor activated serine-threonine kinase, controls various cellular processes including proliferation and survival. However, PKB function in thymocyte development is still unclear. We report PKB as an important negative regulator of the calcineurin (CN)-regulated transcription factor NFAT in early T cell differentiation. Expression of a hyperactive version of CN induces a profound block at the CD25+CD44- double-negative (DN) 3 stage of T cell development. We correlate this arrest with up-regulation of Bcl-2, CD2, CD5, and CD27 proteins and constitutive activation of NFAT but a severe impairment of Rag1, Rag2, and intracellular TCR-beta as well as intracellular TCR-gammadelta protein expression. Intriguingly, simultaneous expression of active myristoylated PKB inhibits nuclear NFAT activity, restores Rag activity, and enables DN3 cells to undergo normal differentiation and expansion. A correlation between the loss of NFAT activity and Rag1 and Rag2 expression is also found in myristoylated PKB-induced CD4+ lymphoma cells. Furthermore, ectopic expression of NFAT inhibits Rag2 promoter activity in EL4 cells, and in vivo binding of NFATc1 to the Rag1 and Rag2 promoter and cis-acting transcription regulatory elements is verified by chromatin immunoprecipitation analysis. The regulation of CN/NFAT signaling by PKB may thus control receptor regulated changes in Rag expression and constitute a signaling pathway important for differentiation processes in the thymus and periphery.
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PMID:PKB rescues calcineurin/NFAT-induced arrest of Rag expression and pre-T cell differentiation. 1698 94

Calcium is a second messenger for many signaling pathways in B cells, but its role as a receptor ligand has not been well characterized. However, pulses of free calcium were found to cause the rapid release of internal calcium stores in normal human B cells. This response appeared to be mediated by a cell surface protein with receptor properties as it could be blocked by pretreatment with trypsin and with kinase and phospholipase Cgamma inhibitors. The calcium receptor on B cells was not the conventional calcium-sensing receptor (CaSR) since B cells did not express CaSR and calcium-induced responses could not be blocked by specific CaSR inhibitors. B-cell responses to extracellular calcium activated phosphoinositide-3 kinase/AKT, calcineurin, extracellular signal regulated kinase, p38 mitogen-activated protein kinase, protein kinase C, Ca(2+)/calmodulin kinase II, and nuclear factor-kappaB signaling pathways, and resulted in transcription of the early response gene, CD83. This extracellular calcium sensor enhanced B-cell responses to Toll-like receptor, B-cell receptor, and cytokine receptor agonists. These findings suggest a means by which B cells prepare to engage in immune responses by responding to calcium fluctuations in their environment.
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PMID:Extracellular calcium sensing promotes human B-cell activation and function. 1772 42

T cell receptor (TCR) and costimulatory receptor (CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells (NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine-threonine kinase AKT, thereby enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice, which also developed autoimmune-like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self-reactivity.
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PMID:NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. 1821 1

An F(1) mutagenesis strategy was developed to identify conditional mutations affecting extracellular matrix (ECM) patterning. Tubulogenesis requires coordinated movement of epithelial cells and deposition of a multilayered ECM. In the Drosophila ovary, an epithelium of follicle cells creates the eggshells, including the paired tubular dorsal appendages (DAs) that act as breathing tubes for the embryo. A P-element mutagenesis strategy allowed for conditional overexpression of hundreds of genes in follicle cells. Conditional phenotypes were scored at the level of individual mutant (F(1)) female flies. ECM pattern regulators were readily identified including MAPK signaling gene ets domain lacking (fused DAs), Wnt pathway genes frizzled 3 and osa (long DAs), Hh pathway gene debra (branched DAs), and transcription factor genes sima/HIF-1alpha, ush, lilli, Tfb1, broad, and foxo. In moving cells the [Ca(2+)]/calcineurin pathway can regulate adhesion to ECM while adherens junctions link cells together. Accordingly, thin eggshell and DA phenotypes were identified for the calcineurin regulator calreticulin and the adherens junction component arc. Finally a tubulogenesis defect phenotype was identified for the gene pterodactyl, homologous to the mammalian serine/threonine receptor-associated protein (STRAP) that integrates the TGF-beta and PI3K/AKT signaling pathways. Because phenotypes can be scored in each mutant fly before and after gene induction, this F(1) conditional mutagenesis strategy should allow for increased scale in screens for mutations affecting repeated (reiterated) events in adult animals, including gametogenesis, movement, behavior, and learning.
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PMID:Conditional switches for extracellular matrix patterning in Drosophila melanogaster. 1824 54

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is mutated or lost in 60% to 70% of advanced gliomas and is associated with malignant phenotypic changes such as migration, which contribute to the morbidity and mortality of this disease. Most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Despite recent work suggesting that the protein phosphatase activity of PTEN controls glioma cell migration, the mechanisms by which this occurs are unclear. Herein, we show using glioma cell lines (U87MG and U373MG) stably transfected with wild-type PTEN or catalytically altered mutants of PTEN that PTEN controls integrin-directed migration in a lipid phosphatase, PI3K/AKT-independent manner. Confirming this observation, we show that the stable overexpression of COOH-terminal Src kinase, the physiologic negative regulator of SRC family kinases (SFK), or treatment with the SFK inhibitor PP1 abrogates glioma migration. The results provide direct evidence that the downstream effect of the protein phosphatase activity of PTEN is to suppress SFK and FYN, and to regulate RAC-GTPase activity after alpha(v) integrin stimulation. Furthermore, studying vitronectin-directed migration using (a) Fyn small interfering RNA and (b) astrocytes from Fyn heterozygous (+/-) mice, Pten heterozygous (+/-) mice, Pten and Fyn double heterozygous (+/-) mice, or Fyn knockout (-/-) mice confirmed a role of FYN in alpha(v) integrin-mediated haptotaxis in glial cells. Our combined results provide direct biochemical and genetic evidence that PTEN's protein phosphatase activity controls FYN kinase function in glioma cells and regulates migration in a PI3K/AKT-independent manner.
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PMID:The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. 1833 67

Since its discovery in 1997, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has become one of the most important molecules in tumor biology. Mutations, deletions or dysregulation of PTEN is found in many human tumors. Recent studies have extended the reach of PTEN to include diabetes and neurological diseases such as Parkinson's and autism. In this review, we summarize the traditionally characterized function of PTEN as the lipid phosphatase that dephosphorylates PI-3,4,5-P(3), and several other newly discovered functions. The inhibition of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway may account for most of PTEN's tumor suppressing function. However, other growth inhibiting functions of PTEN may not involve this pathway. PTEN can also inhibit growth through its protein phosphatase activity and in ways not related to its enzymatic activity at all. We survey the many functions and biochemical interactions of PTEN in cytoplasm, the nucleus and throughout the cell in this paper.
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PMID:Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. 1895 Jul 30

Protein phosphatase 2A (PP2A) is a heterotrimer comprising catalytic, scaffold, and regulatory (B) subunits. There are at least 21 B subunit family members. Thus PP2A is actually a family of enzymes defined by which B subunit is used. The B56 family member B56alpha is a phosphoprotein that regulates dephosphorylation of BCL2. The stress kinase PKR has been shown to phosphorylate B56alpha at serine 28 in vitro, but it has been unclear how PKR might regulate the BCL2 phosphatase. In the present study, PKR regulation of B56alpha in REH cells was examined, because these cells exhibit robust BCL2 phosphatase activity. PKR was found to be basally active in REH cells as would be predicted if the kinase supports B56alpha-mediated dephosphorylation of BCL2. Suppression of PKR promoted BCL2 phosphorylation with concomitant loss of B56alpha phosphorylation at serine 28 and inhibition of mitochondrial PP2A activity. PKR supports stress signaling in REH cells, as suppression of PKR promoted chemoresistance to etoposide. Suppression of PKR promoted B56alpha proteolysis, which could be blocked by a proteasome inhibitor. However, the mechanism by which PKR supports B56alpha protein does not involve PKR-mediated phosphorylation of the B subunit at serine 28 but may involve eIF2alpha activation of AKT. Phosphorylation of serine 28 by PKR promotes mitochondrial localization of B56alpha, because wild-type but not mutant S28A B56alpha promoted mitochondrial PP2A activity. Cells expressing wild-type B56alpha but not S28A B56alpha were sensitized to etoposide. These results suggest that PKR regulates B56alpha-mediated PP2A signaling in REH cells.
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PMID:PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells. 1895 15

PTEN is a dual lipid and protein phosphatase that antagonizes PI3K as well as other signaling pathways and regulates cellular survival and growth. However, its potential role in cardiac ischemia/reperfusion injury remains unknown. We established a transgenic mouse model with inducible and cardiac specific deletion of Pten gene (Pten(CKO)) in adult heart via tamoxifen dependent Cre-loxP mediated DNA recombination. 3 weeks after tamoxifen induced PTEN inactivation, elevated PI3K activity was observed in the Pten(CKO) hearts as determined from downstream AKT signaling. No significant differences in cardiac function as well as chamber size were observed between Pten(CKO) and Control animals based on echocardiography. In response to 30 min ischemia followed by 120 min reperfusion in Langendorff preparations, Pten(CKO) hearts developed significantly better function recovery than Control animals. At 60 min post reperfusion, the recovery of LVDP reached 77.9% of pre-ischemia basal in Pten(CKO) hearts vs 44.2% of Control (p<0.01). Consistent with the observed functional improvement, TTC staining revealed a significant reduction in infarct size in Pten(CKO) hearts compared with Control (24.2% vs 39.7%, p<0.05). Pten(CKO) hearts had significantly fewer apoptosis positive cardiomyocytes after I/R injury as identified by TUNEL staining. Furthermore, ERK activity and BCL-2 expression were not affected at basal but became significantly higher after ischemia/reperfusion in Pten(CKO) hearts. These data indicate that PTEN may play a role in ischemia/reperfusion injury by inhibiting anti-apoptotic survival signals. Inhibiting PTEN may serve as a potential approach to exert cardiac protection against ischemia reperfusion injury.
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PMID:Inducible and cardiac specific PTEN inactivation protects ischemia/reperfusion injury. 1903 62


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