Calcineurin: Form and Function

Rusnak, Frank; Mertz, Pamela

doi:10.1152/physrev.2000.80.4.1483

Cited by 1,233 publications

(1,118 citation statements)

References 460 publications

(318 reference statements)

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“…The mitochondrial permeability transition may be induced by oxidative stress and is increasingly recognised as an element of cell necrosis (Lemasters et al, 1998;Lemasters, 1999). This transition may be blocked by cyclosporin A, an inhibitor of calcineurin, with which dermcidin shares a homologous phosphatase domain (Cunningham et al, 1998;Rusnak and Mertz, 2000), raising the possibility that this may be the point at which dermcidin acts on the necrotic pathway. The structural effects of the asparagine residues which influence the function of dermcidin have not been determined in the present study.…”

Section: Discussionmentioning

confidence: 99%

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

et al. 2006

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Proteolysis-inducing factor, a cachexia-inducing tumour product, is an N-glycosylated peptide with homology to the unglycosylated neuronal survival peptide Y-P30 and a predicted product of the dermcidin gene, a pro-survival oncogene in breast cancer. We aimed to investigate whether dermcidin is pro-survival in liver cells, in which proteolysis-inducing factor induces catabolism, and to determine the role of potentially glycosylated asparagine residues in this function. Reverse cloning of proteolysis-inducing factor demonstrated B100% homology with the dermcidin cDNA. This cDNA was cloned into pcDNA3.1 þ and both asparagine residues removed using site-directed mutagenesis. In vitro translation demonstrated signal peptide production, but no difference in molecular weight between the products of native and mutant vectors. Immunocytochemistry of HuH7 cells transiently transfected with V5-His-tagged dermcidin confirmed targeting to the secretory pathway. Stable transfection conferred protection against oxidative stress. This was abrogated by mutation of both asparagines in combination, but not by mutation of either asparagine alone. These findings suggest that dermcidin may function as an oncogene in hepatic as well as breast cells. Glycosylation does not appear to be required, but the importance of asparagine residues suggests a role for the proteolysis-inducing factor core peptide domain.

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Section: Discussionmentioning

confidence: 99%

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

et al. 2006

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“…Calcineurin or protein phosphatase 2B (PP-2B) is a serine/threonine phosphatase (Rusnak and Mertz, 2000) and is unique among other phosphatases of its family (PPI and PP2) in that Ca 2+ -calmodulin is required for its activation. PP-2B dephosphorylates (on multiples serines) the transcription complex NFAT, exposing its nuclear localization signal (Crabtree, 2001;Rao et al, 1997).…”

Section: Calcium/calmodulin Pathwaymentioning

confidence: 99%

“…PP2-B is a serine/threonine phosphatase (Rusnak and Mertz, 2000) and is unique among other phosphatases of its family (PPI and PP2) in its dependency on Ca 2+ /calmodulin for its activation. NFAT is expressed in the rat pancreatic β cell (Lawrence et al, 2002) and the dephosphorylated NFAT complex is maintained in the nucleus as long as Ca 2+ concentrations are elevated, thus maintaining calcineurin in the activated state (Timmerman et al, 1996).…”

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

560

454

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…PP2B/calcineurin is a dimeric phosphatase composed of a catalytic subunit (A) and a regulatory subunit (B) [25,55]. The catalytic subunit is activated by binding to the calcium/ calmodulin complex.…”

Section: Regulation Of Extracellular Adenosine By Phosphatase 1/2a Bmentioning

confidence: 99%

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

Rosenberg

2007

Brain Research

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We have previously demonstrated that NMDA receptor-mediated extracellular adenosine accumulation in neuronal cultures is receptor-mediated and requires calcium influx. Because protein kinase C (PKC) is a calcium-dependent enzyme, we hypothesized that activation of PKC might be involved in NMDA-mediated adenosine accumulation. PKC inhibitors however, did not block NMDA-evoked adenosine accumulation, but rather, stimulated basal adenosine accumulation. These data suggested the possibility that NMDA receptor mediated adenosine accumulation involves net dephosphorylation rather than phosphorylation of one or more substrates. Thus, inhibition of kinases would be expected to increase adenosine accumulation and inhibition of phosphatases would be expected to block adenosine accumulation. To test this hypothesis, we used the phosphatase 1/2A inhibitors calyculin A and okadaic acid. Both inhibitors significantly reduced NMDA-evoked adenosine accumulation. In contrast phosphatase 2B inhibitors did not block NMDA-evoked adenosine accumulation. These data suggest that NMDAevoked adenosine accumulation is mediated by activation of phosphatase 1/2A. We have established previously that NMDA-mediated adenosine accumulation is associated with adenosine kinase inhibition. However, adenosine kinase is not a direct substrate for phosphatase 1/2A because inhibition of phosphatase 1/2A did not abolish NMDA-evoked adenosine kinase inhibition. Okadaic acid also had no effect on NO donor-evoked adenosine accumulation, which previously has been shown to be associated with adenosine kinase inhibition. Dephosphorylation of one or more proteins other than adenosine kinase as a consequence of NMDA receptor activation might play an important role in extracellular adenosine regulation, with important consequences for the regulation of excitatory synaptic transmission, plasticity, epileptogenesis, and excitotoxicity.

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Calcineurin: Form and Function

Cited by 1,233 publications

References 460 publications

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

Mechanisms of action of glucagon-like peptide 1 in the pancreas

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

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