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)

Kisspeptins, a family of peptide products derived from the KiSS-1 gene, activate their cognate receptor GPR54 in various target tissues to exert disparate functions, including inhibition of tumor metastasis and control of reproductive function. In contrast to the plethora of studies that have analyzed in recent years the regulatory functions of the KiSS-1/GPR54 system, only a limited number of reports have been primarily focused on delineating the intracellular signaling pathways involved. Nevertheless, there is solid evidence indicating that kisspeptin can activate a wide variety of signals via GPR54. These include typical G-protein (Galphaq/11)-coupled cascades, such as activation of phospholipase C (PLC), and subsequent accumulation of inositol-(1,4,5)-triphosphate (IP3), intracellular Ca(2+) mobilization, and activation of protein kinase C. However, kisspeptin also activates pathways related to mitogen activated protein kinases (MAPK), especially ERK1/2, and p38 and phosphatidylinositol-3-kinase (PI3K)/Akt. Additionally, the kisspeptin/GPR54 pair can also influence cell signaling by interacting with other receptors, such as chemokine receptor CXCR4, and GnRH receptor. Kisspeptin can also affect other signaling events, like expression of matrix metalloproteinase 9 (via NFkappaB), and that of calcineurin. The information gathered hitherto clearly indicates that activation of a specific set of interconnected signals is selectively triggered by kisspeptin via GPR54 in a cell type-dependent manner to precisely regulate functions as distinct as hormone release and cell migration. In this scenario, it will be important to decipher kisspeptin/GPR54 signaling mechanisms in reproductive and non-reproductive tissues by studying additional models, especially on natural kisspeptin targets expressing endogenous GPR54.
...
PMID:Intracellular signaling pathways activated by kisspeptins through GPR54: do multiple signals underlie function diversity? 1877 60

Sphingosine kinase 1 (SK1) is an important regulator of cellular signaling that has been implicated in a broad range of cellular processes. Cell exposure to a wide array of growth factors, cytokines, and other cell agonists can result in a rapid and transient increase in SK activity via an activating phosphorylation. We have previously identified extracellular signal-regulated kinases 1 and 2 (ERK1/2) as the kinases responsible for the phosphorylation of human SK1 at Ser(225), but the corresponding phosphatase targeting this phosphorylation has remained undefined. Here, we provide data to support a role for protein phosphatase 2A (PP2A) in the deactivation of SK1 through dephosphorylation of phospho-Ser(225). The catalytic subunit of PP2A (PP2Ac) was found to interact with SK1 using both GST-pulldown and coimmunoprecipitation analyses. Coexpression of PP2Ac with SK1 resulted in reduced Ser(225) phosphorylation of SK1 in human embryonic kidney (HEK293) cells. In vitro phosphatase assays showed that PP2Ac dephosphorylated both recombinant SK1 and a phosphopeptide based on the phospho-Ser(225) region of SK1. Finally, both basal and tumor necrosis factor-alpha-stimulated cellular SK1 activity were regulated by molecular manipulation of PP2Ac activity. Thus, PP2A appears to function as an endogenous regulator of SK1 phosphorylation.
...
PMID:Deactivation of sphingosine kinase 1 by protein phosphatase 2A. 1885 66

Serine/threonine protein phosphatases are important mediators of general cellular function as well as neurodegenerative processes. We have previously shown inhibition of protein phosphatases to be as neurotoxic as glutamate-induced neuronal death but resistant to neuroprotection by estrogens. In this study, the mechanism by which phosphatase inhibition via okadaic acid (OA) induced neurotoxicity is explored. Neurons were exposed to OA or glutamate in the presence or absence of various protein kinases inhibitors, and/or one of four estrogens. Both OA and glutamate induced cell death via increased reactive oxygen species, protein carbonylation, lipid peroxidation, caspase-3 activity, and mitochondrial dysfunction. All estrogens attenuated glutamate-mediated responses, but not OA-induced responses. In addition, inhibition of protein kinase C and mitogen-activated protein kinase pathway was neuroprotective against glutamate but not OA toxicity. Interestingly, inhibition of mitogen-activated protein kinase pathway with PD98096 or U0126 caused a decrease in reactive oxygen species production suggesting that activation of ERK1/2 could further exacerbate the oxidative stress caused by glutamate-induced toxicity; however, these inhibitors had no effect on OA-induced toxicity. Collectively, these results indicate that both glutamate and OA neurotoxicities are mediated by persistent activation of ERK1/2 and/or protein kinase C and a resulting oxidative stress, and that protein phosphatase activity is an important and necessary aspect of estrogen-mediated neuroprotection.
...
PMID:Mechanism of okadaic acid-induced neuronal death and the effect of estrogens. 1905 78

Phosphorylation of the dopamine transporter (DAT) on N-terminal serines and unidentified threonines occurs concomitantly with protein kinase C (PKC)- and substrate-induced alterations in transporter activity, subcellular distribution, and dopamine efflux, but the residues phosphorylated and identities of protein kinases and phosphatases involved are not known. As one approach to investigating these issues, we recombinantly expressed the N-terminal tail of rat DAT (NDAT) and examined its phosphorylation and dephosphorylation properties in vitro. We found that NDAT could be phosphorylated to significant levels by PKCalpha, PKA, PKG, and CaMKII, which catalyzed serine phosphorylation, and ERK1, JNK, and p38, which catalyzed threonine phosphorylation. We identified Thr53, present in a membrane proximal proline-directed kinase motif as the NDAT site phosphorylated in vitro by ERK1, JNK and p38, and confirmed by peptide mapping and mutagenesis that Thr53 is phosphorylated in vivo. Dephosphorylation studies showed that protein phosphatase 1 catalyzed near-complete in vitro dephosphorylation of PKCalpha-phosphorylated NDAT, similar to its in vivo and in vitro effects on native DAT. These findings demonstrate the ability of multiple enzymes to directly recognize the DAT N-terminal domain and for kinases to act at multiple distinct sites. The strong correspondence between NDAT and rDAT phosphorylation characteristics suggests the potential for the enzymes that are active on NDAT in vitro to act on DAT in vivo and indicates the usefulness of NDAT for guiding future DAT phosphorylation analyses.
...
PMID:Proline-directed phosphorylation of the dopamine transporter N-terminal domain. 1914 7

The immunosuppressant cyclosporine A (CsA) is a specific pharmacological inhibitor of calcineurin, the Ca2+-calmodulin activated phospho-Ser/Thr-specific protein phosphatase. Although calcineurin-inhibiting compounds are applied for local treatment of psoriasis or atopic dermatitis in dermatological practice, little is known about the functions of calcineurin in epidermis-derived malignancies. We investigated the effects of CsA on two human melanoma cell lines, the metastasis forming HT168 and WM35 established from an RGP primary lesion. CsA of 2 microM lowered the enzyme activity by 50% and caused elevation in both mRNA and protein expression of calcineurin. Cell proliferation was diminished, as well as the cellular morphology and the actin organization were altered in both cell lines. CsA increased cell death moderately in both cell lines and reduced the metabolic activity of HT168 cells, but not that of WM35 cells. CsA also elevated the expressions of both Bcl-2 and ERK1/2. Fibronectin guided migration of HT168 cells was stimulated under the effect of CsA, while that of WM35 cells was reduced, moreover, HT168 cells switched from the expression of beta3 to beta1 integrin, but WM35 cells continued to express beta3. Based on our results we propose a multiple, partly malignancy-dependent role of calcineurin in these melanoma cell lines.
...
PMID:Inhibition of calcineurin by cyclosporine A exerts multiple effects on human melanoma cell lines HT168 and WM35. 1928 56

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Although the precise mechanism remains unclear, mounting evidence suggests that oxidative stress plays an important role in the pathogenesis of PD. DJ-1 gene is associated with oxidative stress and mutations in DJ-1 are involved in an autosomal recessive, early onset familial form of PD. The ERK1/2 signaling pathway contributes to neuroprotection during oxidative stress. However, the correlation between DJ-1 and the ERK1/2 signaling pathway remains unknown. To test for an association of DJ-1 with the ERK1/2 signaling pathway, we transfected wild-type and L166P mutated DJ-1 into COS-7 and MN9D cells. The results showed that over-expression of WT-DJ-1 dramatically enhanced the phosphorylation of ERK1/2 and its upstream kinase MEK1/2. Meanwhile, WT-DJ-1, but not L166P-DJ-1 inhibited the expression of protein phosphatase 2A (PP2A), an inhibitor of the ERK1/2 signaling pathway. Moreover, over-expression of WT-DJ-1 increased cell viability and decreased cell sensitivity to H2O2-induced neurotoxicity. Inhibition of the ERK1/2 signaling pathway with a MEK1/2 inhibitor reversed these changes. We conclude that DJ-1 does affect the ERK1/2 signaling pathway and change the susceptibility of cells to oxidative stress.
...
PMID:Involvement of ERK1/2 signaling pathway in DJ-1-induced neuroprotection against oxidative stress. 1937 28

MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between -380 and -180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS- or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.
...
PMID:CREB and AP-1 activation regulates MKP-1 induction by LPS or M-CSF and their kinetics correlate with macrophage activation versus proliferation. 1958 11

Physical exercise triggers the release of several cytokines/chemokines from working skeletal muscles, but the underlying mechanism(s) by which skeletal muscles decipher and respond to highly complex contractile stimuli remains largely unknown. In an effort to investigate the regulatory mechanisms of the expressions of two contraction-inducible CXC chemokines, CXCL1/KC and CXCL5/LIX, in contracting skeletal muscle cells, we took advantage of our in vitro exercise model using highly developed contractile C(2)C(12) myotubes, which acquire properties similar to those of in vivo skeletal muscle via manipulation of Ca(2+) transients with electric pulse stimulation (EPS). Production of these CXC chemokines was immediately augmented by EPS-evoked contractile activity in a manner dependent on the activities of JNK and NF-kappaB, but not p38, ERK1/2, or calcineurin. Intriguingly, exposure of myotubes to cyclic mechanical stretch also induced expression of these CXC chemokines; however, a much longer period of stimulation (approximately 12 h) was required, despite rapid JNK phosphorylation. We also demonstrate herein that CXCL1/KC and CXCL5/LIX have the ability to raise intracellular Ca(2+) concentrations via CXCR2-mediated activation of pertussis toxin-sensitive Galpha(i) proteins in C(2)C(12) myoblasts, an action at least partially responsible for their migration and differentiation. Although we revealed a possible negative feedback regulation of their own production in response to the contractile activity in differentiated myotubes, exogenous administration of these CXC chemokines did not acutely influence either insulin-induced Akt phosphorylation or GLUT4 translocation in C(2)C(12) myotubes. Taken together, these data shed light on the fundamental characteristics of contraction-inducible CXC chemokine production and their potential roles in skeletal muscle cells.
...
PMID:Characterization of contraction-inducible CXC chemokines and their roles in C2C12 myocytes. 1962 86

A gain of function mutation in SHP2, a protein phosphatase encoded by PTPN11, causes Noonan syndrome (NS), which is characterized in part by developmental deficits in both the cardiac and skull fields. Previously, we found that expression of the mutated protein SHP2 Q79R in the heart led to a phenotypic presentation that mimicked some aspects of NS and that this was dependent upon activation of the ERK1/2 pathway. To understand the role that ERK1/2 signaling plays in skull development through signaling in the neural crest, we explored the consequences of Q79R expression in neural crest cells, which contribute to a subset of the bony and cartilaginous structures of the skull. Hyperactivation of ERK1/2 led to craniofacial defects that included smaller skull lengths, greater inner canthal distances, and taller frontal bone heights. In proportion to the smaller skull length, mandibular bone length was also reduced. Inhibition of ERK1/2 hyperactivity as a result of Q79R expression was achieved by injection of the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively decreased the severity of the craniofacial defects and restored normal skull shape and fontanelle closure. X-ray computer-assisted microtomography analysis of the head confirmed that decreasing ERK1/2 activity led to an abrogation of the craniofacial deficits and brain shape changes that presented in the mice. These data show that normal ERK1/2 signaling in the neural crest is imperative for normal craniofacial development and offer insight into how the heart and craniofacial developmental fields might be affected in some congenital syndromic presentations.
...
PMID:Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. 1970 3

A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.
...
PMID:Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization. 1976 70


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

---