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

---

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

The signal transducers and activators of transcriptions (Stats) are central mediators of cytokine responses especially in hematopoietic cells. The detailed molecular mechanisms of Stat activation, particularly the role of post-translational modifications and co-operation with cellular transcription factors are subject to intense investigation. The phosphorylation of a tyrosine residue in the carboxyl terminal domain is a common characteristic for the biologically active state of all known Stats. We studied the biological potential of purified recombinant murine Stat5a and Stat5b. These proteins were expressed in Sf9 insect cells upon infection with Stat5 encoding baculoviruses. We also obtained the tyrosine phosphorylated, activated forms of the Stat5 proteins by expressing the tyrosine kinase Janus kinase2 (Jak) in the same cells through co-infection with a kinase encoding virus. After purification, only the tyrosine phosphorylated form was able to bind specifically in vitro to the Stat5 DNA response element. This activated form of Stat5 is also able to support specific cell free in vitro transcription of a gene with a Stat5 response element in its promoter region. The recombinant purified Stat5 proteins were treated with the tyrosine specific protein phosphatase or with potato acidic phosphatase, which removes phosphate groups from serine and tyrosine residues. Phosphatase treatment resulted in the loss of specific DNA binding ability. This property could be restored by an in vitro reaction with recombinant, purified EGF or PDGF receptor kinases. Tyrosine rephosphorylation in vitro also restored the transactivation potential of Stat5. This modification is, therefore, a sufficient prerequisite for transcriptional induction by Stat5.
...
PMID:Specific DNA binding and transactivation potential of recombinant, purified Stat5. 1160 30

To analyze the implication of PTEN in the control of tumor cell invasiveness, the canine kidney epithelial cell lines MDCKras-f and MDCKts-src, expressing activated Ras and a temperature-sensitive v-Src tyrosine kinase, respectively, were transfected with PTEN expression vectors. Likewise, the human PTEN-defective glioblastoma cell lines U87MG and U373MG, the melanoma cell line FM-45, and the prostate carcinoma cell line PC-3 were transfected. We demonstrate that ectopic expression of wild-type PTEN in MDCKts-src cells, but not expression of PTEN mutants deficient in either the lipid or both the lipid and protein phosphatase activities, reverted the morphological transformation, induced cell-cell aggregation, and suppressed the invasive phenotype in an E-cadherin-dependent manner. In contrast, overexpression of wild-type PTEN did not counteract Ras-induced invasiveness of MDCKras-f cells expressing low levels of E-cadherin. PTEN effects were not associated with marked changes in accumulation or phosphorylation levels of E-cadherin and associated catenins. Wild-type, but not mutant, PTEN also reverted the invasive phenotype of U87MG, U373MG, PC-3, and FM-45 cells. Interestingly, PTEN effects were mimicked by N-cadherin-neutralizing antibody in the glioblastoma cell lines. Our data confirm the differential activities of E- and N-cadherin on invasiveness and suggest that the lipid phosphatase activity of PTEN exerts a critical role in stabilizing junctional complexes and restraining invasiveness.
...
PMID:The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness. 1175 67

The activity of biogenic amine and amino acid neurotransmitters is limited by presynaptic and astrocytic Na(+)-dependent transport systems. Their functional importance is underscored by the observation that these transporters are the targets of broad classes of psychotherapeutic agents, including antidepressants and stimulants. Early studies suggested that the activity of these transporters can be fine tuned by a number of different signaling pathways. In the past five years, several groups have provided compelling evidence that changing the cell surface availability of these transporters contributes to this fine tuning. This regulated trafficking can result in rapid (within minutes) increases or decreases in the plasma membrane expression of these transporters and is independent of transcriptional or translational control mechanisms. Many of the same signaling molecules, including protein kinase C (PKC), tyrosine kinase, phosphatidylinositol 3-kinase (P13-K), and protein phosphatase, regulate the transporters for different neurotransmitters. In addition to these classical receptor activated pathways, transporter substrates also regulate activity and cell surface expression of these transporters. In fact, some of the transporters form complexes with signaling molecules. Given the functional and genetic similarities of these transporters, it is not surprising that the same signaling molecules regulate their trafficking, but except for the molecules, the actual effects on individual transporters are remarkably different. It is as if the same musical notes have been rearranged into several different melodies.
...
PMID:Regulated trafficking of neurotransmitter transporters: common notes but different melodies. 1179 38

Selectins are mediating transient contacts of leukocytes with endothelium during inflammatory processes and in the development of the immune system. L-selectin expressed on almost all leukocytes also functions as a signaling receptor. Recently, we have identified different signaling pathways in T lymphocytes by L-selectin. One signaling cascade leads via the tyrosine kinase p56lck to the small G-proteins Ras and Rac and to MAP-kinases. A second independent pathway results in ceramide release. In this study, an L-selectin-induced translocation of the transcription factor NFAT to the nucleus was identified. Using genetically modified JCaM1.6 cells, pharmacological inhibitors, and antisense molecules, it was shown that L-selectin-induced NFAT activation depends on src-tyrosine kinases, calcineurin and small G-proteins. MAP-kinases and actin filaments were identified as Ras effectors involved in NFAT translocation. We conclude that L-selectin cross-linking results in activation of NFAT by different signaling pathways. The activation of NFAT might modulate the immune response of leukocytes interacting with endothelial cells.
...
PMID:Mechanisms of L-selectin-induced activation of the nuclear factor of activated T lymphocytes (NFAT). 1184 96

We had previously shown that murine macrophages expressing v-Fes, the oncogenically activated counterpart of the c-Fes cytoplasmic tyrosine kinase, proliferate independently of Macrophage Colony-Stimulating Factor (MCSF) and that the Extracellular signal-Regulated Kinase (ERK) pathway mediates the mitogenic effect of v-Fes. In this study, the response of c-fes- and v-fes-overexpressing cells to MCSF was investigated. A critical modulation of the activation of Mitogen-activated ERK Kinase (MEK) and ERK based on the MCSF dose was characterized. ERK activation was increased by MCSF doses capable to elicit a mitogenic response (2-5 U/ml). On the contrary, MCSF doses as low as 0.05 U/ml markedly reduced ERK phosphorylation and nuclear content and moderately but significantly reduced cell proliferation. The reduction of MEK and ERK phosphorylation was very rapid, suggesting the involvement of cytosolic phosphatases. Among these, phospho-tyrosine protein phosphatases and phosphoserine/threonine protein phosphatase-2A were found involved. These findings represent the first observation that different doses of the same growth factor, MCSF in particular, can exert opposite effects on cell proliferation by switching on or off ERK signaling.
...
PMID:Opposite effects of different doses of MCSF on ERK phosphorylation and cell proliferation in macrophages. 1203 35

During the process of capacitation, spermatozoa go through a whole set of signaling cascade events in order to become fully competent at fertilizing the egg. An increase in sperm protein tyrosine phosphorylation has been described during this final maturational event in different animal species as well as in humans. Although the phosphotyrosine content of sperm protein is modulated by cAMP, Ca(2+), BSA, oxygen derivatives, and cholesterol, no protein tyrosine kinase (PTK) nor the phosphotyrosine protein phosphatase (PTPase) directly involved in the control of the phosphotyrosine content of sperm protein has been identified. Therefore, the goal of the present study was to identify the tyrosine kinases putatively responsible for the increases in sperm protein phosphotyrosine content. In the present study, we show that the src-related tyrosine kinase c-yes is present in the head of human spermatozoa in both membranes and Triton X-100-insoluble extracts. Our hypothesis was that c-yes is a tyrosine kinase responsible for at least some of the capacitation-induced increase in protein tyrosine phosphorylation. When spermatozoa were previously incubated in the presence of 3-isobutyl-1-methylxanthine or 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, treatments known to increase the phosphotyrosine content of human sperm proteins, an increase in the kinase activity of immunoprecipitated yes was measured using enolase as a substrate. These results suggest that cAMP activates while Ca(2+) inhibits human sperm c-yes kinase activity.
...
PMID:Regulation of the human sperm tyrosine kinase c-yes. Activation by cyclic adenosine 3',5'-monophosphate and inhibition by Ca(2+). 1208 32

The muscarinic cholinergic receptor (mAChR) subtypes share high sequence similarity except in their third intracellular loop and COOH terminus, domains thought to be involved in signal transduction. Subtypes M1, M3, and M5 couple mainly through Galpha(q/11), and M2 and M4 couple mainly through Galpha(i/o). Whether subtypes within each of these two groups differ in their signaling pathways remains to be resolved. This study focused on nuclear signaling pathways leading to activation of the transcription factor, serum response factor (SRF). Genes encoding M1, M2, and M3 were co-expressed in Jurkat T lymphocytes with a reporter gene driven by a mutant serum response element, SRE.L, which responds to SRF activation. We show that only M1 mAChR activated SRF through a pathway involving the small GTPase RhoA, with no response observed for M2 and M3. Transfection of GTPase-deficient Galpha subunits (GalphaQL; constitutively active form) demonstrated that SRF was activated by Galpha(13)QL but only marginally by Galpha(q)QL and Galpha(12)QL in Jurkat cells. Yet transfection of regulator of G protein-signaling protein, RGS2 and RGS4, which inhibit Galpha(q/11) activity, indicated that Galpha(q/11) and Ca(2+) mobilization were required for SRF activation by M1. Calmodulin inhibitors suppressed the M1 and the Galpha(13)QL pathways, acting both upstream and downstream of RhoA. However, calcineurin inhibitors and the tyrosine kinase inhibitor genistein selectively suppressed SRF activation by M1, but not by Galpha(13)QL, indicating the presence of separate pathways. The calmodulin-dependent tyrosine kinase Pyk2 was also activated by M1 but not M3, and Pyk2 appears also to play a role in M1-SRF activation, as judged by experiments with two dominant-negative Pyk2 mutants. These results reveal a novel calmodulin-dependent RhoA-SRF signaling pathway unique to the M1 mAChR subtype.
...
PMID:Serum response factor activation by muscarinic receptors via RhoA. Novel pathway specific to M1 subtype involving calmodulin, calcineurin, and Pyk2. 1220 Apr 18

Protein kinases and protein phosphatases exert coordinated control over many essential cellular processes. Here, we describe the cloning and characterization of a novel human transmembrane protein KPI-2 (Kinase/Phosphatase/Inhibitor-2) that was identified by yeast two-hybrid using protein phosphatase inhibitor-2 (Inh2) as bait. KPI-2 mRNA was predominantly expressed in skeletal muscle. KPI-2 is a 1503-residue protein with two predicted transmembrane helices at the N terminus, a kinase domain, followed by a C-terminal domain. The transmembrane helices were sufficient for targeting proteins to the membrane. KPI-2 kinase domain has about 60% identity with its closest relative, a tyrosine kinase. However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. KPI-2 kinase domain phosphorylated protein phosphatase-1 (PP1C) at Thr(320), which attenuated PP1C activity. KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. Inh2 associated with KPI-2 C-terminal domain with and without PP1C. Thus, KPI-2 is a kinase with sites to associate with PP1C and Inh2 to form a regulatory complex that is localized to membranes.
...
PMID:A novel transmembrane Ser/Thr kinase complexes with protein phosphatase-1 and inhibitor-2. 1239 58

Interferon-alpha (IFN-alpha)-2b is known to have antiproliferative effects on hematological malignant cells, especially chronic myelogenous leukaemia (CML). However, it can induce cytogenetical remissions in a very small percentage of the patients. Also during interferon therapy, resistance can emerge in the CML clones. K562 is an in vitro model cell line transformed from a Ph positive CML patient. It can be induced to differentiate to granulocytic and/or monocytic lineages with certain molecules. IFN-alpha-2b generally exerts its effects on CML cells by Janus family kinases (Jak/Stat) pathway, mostly through tyrosine kinase system. However, there is almost no data on the relevance of serine/threonine (Ser/Thr) protein phosphatase (PP) system in the interferon induced signal transduction pathways. In this study, we investigated serine/threonine protein phosphatases in the IFN-alpha-2b induced K562 cytotoxicity. Trypan blue dye exclusion test and MTT assay were utilised for determining cytotoxicity. IC(50) of IFN-alpha-2b on K562 cells was found to be 600IU/ml. However, no differentiation was determined by analysis of cell surface antigen expressions. Serine/threonine protein phosphatase inhibitors calyculin A (Cal A) and okadaic acid (OKA) augmented the IFN-alpha-2b induced cytotoxicity. Apoptosis assay by the mono-oligonucleosome detection and acridine orange/propidium iodide dye revealed marked apoptosis underlying cytotoxicity. Phosphatase enzyme assay revealed a gradual increase in protein phosphatase 2A (PP2A) activity during interferon induced cytotoxicity. Conversely, immunoblots showed no change in the expression of PP2A catalytic and regulatory subunits. In conclusion, PP2A plays a role in IFN-alpha-2b induced apoptosis of K562 cells and should be investigated as a new window furthermore.
...
PMID:Involvement of protein phosphatase 2A in interferon-alpha-2b-induced apoptosis in K562 human chronic myelogenous leukaemia cells. 1280 29

We have shown that the serine/threonine protein phosphatase 2A (PP2A) associates with the Jak2 tyrosine kinase in a myeloid progenitor line. In this study, we characterized the regions of Jak2 and PP2A responsible for association and evaluated the functional consequences of association. We demonstrate that PP2A interacts with truncated forms of Jak2 containing the JH1 catalytic domain. Using GST fusion proteins, we show that the isolated JH1 and JH3 domains of Jak2 bind directly to PP2A. Jak2 contains putative PP2A binding sequences (LXXLL) in the JH1 domain (residues 1078-1082) and in the JH3 domain (residues 474-478). Mutation of the LXXLL sequence in the JH1 domain decreased PP2A binding in vitro, while mutation of the similar JH3 sequence did not affect PP2A binding. We analyzed full-length Jak2 bearing the LXXLL mutation in Cos-7 cells for association with PP2A. The JH1 mutation impaired Jak2 activity and had a modest effect on PP2A binding. Finally, we show that a mutant form of the PP2A catalytic subunit lacking a site for phosphorylation (Y307F) binds more tightly to Jak2 than wild-type PP2A, consistent with a model where phosphorylation disrupts the Jak2-PP2A interaction.
...
PMID:Determinants for the interaction between Janus kinase 2 and protein phosphatase 2A. 1292 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---