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)

Serine/threonine kinase Akt is a downstream effector protein of phosphatidylinositol-3-kinase (PI-3K). Many integrins can function as positive modulators of the PI-3K/Akt pathway. Integrin alpha 2 beta 1 is a collagen receptor that has been shown to induce specific signals distinct from those activated by other integrins. Here, we found that, in contrast what was found for cells adherent to fibronectin, alpha 2 beta 1-mediated cell adhesion to collagen leads to dephosphorylation of Akt and glycogen synthase kinase 3 beta (GSK3 beta) and concomitantly to the induction of protein serine/threonine phosphatase 2A (PP2A) activity. PP2A activation can be inhibited by mutation in the alpha 2 cytoplasmic domain and by a function-blocking anti-alpha 2 antibody. Akt can be coprecipitated with PP2A, and coexpression of Akt with PP2Ac (catalytic subunit) inhibits Akt kinase activity. Integrin alpha 2 beta 1-related activation of PP2A is dependent on Cdc42. These results indicate that cell adhesion to collagen modulates Akt activity via the alpha 2 beta 1-induced activation of PP2A.
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PMID:Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. 1183 2

Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes. The type I sites correspond to functional receptors involved in endocytosis and the type II sites to sulfated glycosaminoglycans (GAGs). Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs. The peptidyl-prolyl isomerase activity of CyPB is not required for receptor binding. We have recently demonstrated that CyPB enhances adhesion of peripheral blood T-lymphocytes to fibronectin, a component of the extracellular matrix. We intended to identify additional amino acids involved in the binding of CyPB to its functional type I receptor and to determine regions responsible for the stimulation of peripheral blood T-lymphocyte adhesion. We determined that residues R76, G77, K132, D155, and D158 of the calcineurin (CN) interacting region were implicated in the recognition of type I receptor but not of GAGs. We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect. On the other hand, the adhesion of peripheral blood T-lymphocytes to coated fibronectin was not stimulated by CyPB mutants devoid of either type I receptor or GAGs binding activity or by mutants of the PPIase site. Altogether, the results demonstrate that different regions of CyPB are involved in peripheral blood T-lymphocyte activation and imply a novel important physiological function for peptidyl-prolyl isomerase activity.
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PMID:Receptor type I and type II binding regions and the peptidyl-prolyl isomerase site of cyclophilin B are required for enhancement of T-lymphocyte adhesion to fibronectin. 1195 71

Cardiac hypertrophy is characterized by remodeling of the extracellular matrix (ECM). Integrins are cell-surface molecules that link the ECM to the cellular cytoskeleton where they play roles as signaling molecules and transducers of mechanical force. To clarify the possible roles of integrins in cardiac myocyte hypertrophy, we investigated the cellular localization and expression of ECM proteins and integrins in both normal cardiac myocytes and phenylephrine-induced hypertrophic myocytes. Addition of phenylephrine (PE) to cultured neonatal cardiac myocytes induced sarcomeric organization, increase in cell size, and synthesis of the hypertrophic marker, atrial natriuretic factor (ANF). In particular, fibronectin and collagen underwent dramatic localization changes during PE-induced cardiac hypertrophy. Significant changes were noted in the cellular localization of the respective collagen and fibronectin receptors, integrin alpha1 and alpha5, from diffuse to a sarcomeric banding pattern. Expression levels of integrins were also increased during hypertrophy. Treatment with okadaic acid (OA), an inhibitor of protein phosphatase 2A (PP2A), resulted in inhibition of hypertrophic response. These results suggest that dephosphorylation of integrin beta1 may be important in the induction of cardiac hypertrophy.
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PMID:Cellular localization of integrin isoforms in phenylephrine-induced hypertrophic cardiac myocytes. 1257 20

The mechanisms by which T lymphocytes escape apoptosis during their activation are still poorly defined. In this study, we elucidated the intracellular signaling pathways through which beta1 integrins modulate Fas-mediated apoptosis in T lymphocytes. In experiments done in Jurkat T cells and activated peripheral blood T lymphocytes, engagement of alpha2beta1 integrin with collagen type I (Coll I) was found to significantly reduce Fas-induced apoptosis and caspase-8 activation; Annexin V binding and DNA fragmentation were reduced by approximately 42 and 38%, respectively. We demonstrated that the protective action of Coll I does not require new protein synthesis but was dependent on the activation of the MAPK/Erk pathway. Furthermore, we found that activation of protein phosphatase 2A (PP2A) by Coll I was required for both Coll I-mediated activation of Erk, and inhibition of Fas-induced caspase-8 activation and apoptosis. Other ligands of beta1 integrins, fibronectin (Fbn), and laminin (Lam), did not sustain significant Erk activation and had no effect on Fas-induced apoptosis. Taken together, these results provide the first evidence of a PP2A-dependent activation of the MAPK/Erk pathway downstream of alpha2beta1 integrin, which has a functional role in regulating Fas-mediated apoptosis in T lymphocytes. As such, this study emphasizes the potential importance that Coll I interactions may have on the control of T lymphocyte homeostasis and their persistence in chronic inflammatory diseases.
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PMID:Integrin alpha2beta1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway. 1367 75

Tautomycetin (TMC), a newly developed immunosuppressive agent, induces T-lymphocyte apoptosis through the inhibition of tyrosine kinase and protein phosphatase 1. We examined the effects of TMC on platelet-derived growth factor (PDGF)-induced proliferation and extracellular matrix synthesis in cultured vascular smooth muscle cells (VSMCs) and mesangial cells (MCs) of Sprague-Dawley rats, and investigated the molecular mechanisms involved. Different concentrations of TMC were administered 1 hour before the addition of 10 ng/mL PDGF into the growth-arrested and synchronized cells. Cell proliferation was assessed by methylthiazoletetrazolium (MTT) assay, fibronectin secretion, and the activation of Akt, ERK, and p38 MAPK by Western blot analysis. PDGF increased cell proliferation, fibronectin secretion, and the activation of Akt, ERK, and p38 MAPK in both VSMCs and MCs. In both cultured cells, TMC at >1 mug/mL significantly reduced basal MTT. TMC at 100 ng/mL significantly decreased the PDGF-induced VSMC and MC proliferation. However, fibronectin secretion and the activation of Akt, ERK, and p38 MAPK were not affected by this nontoxic concentration of TMC. The present data demonstrate that low-dose TMC reduced PDGF-induced VSMC and MC proliferation without affecting the fibronectin secretion and cellular kinase activation.
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PMID:Effects of tautomycetin on proliferation and fibronectin secretion in vascular smooth muscle cells and glomerular mesangial cells. 1591 17

In addition to tyrosine sites, FAK (focal adhesion kinase) is phosphorylated on multiple serine residues. In the present study, the regulation of two of these sites, Ser-722 (S1) and Ser-911 (S4), was investigated. Phosphorylation of S1 (but not S4) decreased in resuspended cells, and recovered during spreading on fibronectin, indicating adhesion-dependent regulation. GSK3 (glycogen synthase kinase 3) inhibitors decreased S1 phosphorylation, and siRNA (short interfering RNA) silencing indicated further the involvement of GSK3beta. Furthermore, GSK3beta was found to become activated during cell spreading on fibronectin, and to physically associate with FAK. S1 phosphorylation was observed to decrease in wounded cell monolayers, while GSK3beta underwent inactivation and later was observed to increase to the original level within 24 h. Direct phosphorylation of S1, requiring pre-phosphorylation of Ser-726 in the +4 position, was demonstrated using purified GSK3 and a synthetic peptide containing FAK residues 714-730. An inhibitory role for S1 phosphorylation in FAK signalling was indicated by findings that both alanine substitution for S1 and dephosphorylation of S1 by PP1 (serine/threonine protein phosphatase type-1) resulted in an increase in FAK kinase activity; likewise, this role was also shown by cell treatment with the GSK3 inhibitor LiCl. The inhibitory role was confirmed by the finding that cells expressing FAK with alanine substitution for S1 displayed improved cell spreading and faster migration in wound-healing and trans-well assays. Finally, the finding that S1 phosphorylation increased in cells treated with the PP1 inhibitor okadaic acid indicated targeting of this site by PP1. These results indicate an additional mechanism for regulation of FAK activity during cell spreading and migration, involving Ser-722 phosphorylation modulated through the competing actions of GSK3beta and PP1.
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PMID:Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. 1597 92

Growing evidence indicates that interactions of T cells with extracellular matrix through beta1 integrins are important for the regulation of T cell-mediated immune responses and diseases. In this regard, we have recently demonstrated that collagen I (Coll I) through alpha2beta1 integrin inhibited Fas-induced apoptosis of T cells by activating a protein phosphatase 2A (PP2A)-dependent ERK/MAP Kinase pathway. As survival of T cells is critical for their functions, we further investigated the mechanisms underlying the activation of this pathway. Inhibition studies demonstrated that Coll I activates the ERK/MAP Kinase pathway in Jurkat T cells through the activation of Ras and Raf-1. Activation of PP2A was not necessary for the binding of Coll I to Jurkat T cells, but is required for the activation of Raf-1. In accordance, activation of Ras, Raf-1 and PP2A were also required for the ability of Coll I to protect Jurkat T cells from Fas-induced apoptosis. In contrast and despite its capacity to activate Ras, fibronectin (Fbn) failed to activate PP2A and Raf-1. These results might explain, at least in part, the weak ability of Fbn to activate ERK in T cells, supporting thus the differential signaling of beta1 integrin members in these cells. This study provides novel insights into the mechanisms by which beta1 integrins activate the ERK/MAP Kinase pathway in T cells, and is the first report to provide a role for PP2A in integrin-mediated ERK/MAP Kinase activation.
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PMID:Collagen type I-mediated activation of ERK/MAP Kinase is dependent on Ras, Raf-1 and protein phosphatase 2A in Jurkat T cells. 1626 49

1. Cardiac fibroblasts play an important regulatory role in cardiac remodelling by undergoing proliferation, differentiation and upregulating various gene products, including some cytokines and extracellular matrix (ECM) proteins. A highly potent mediator of cardiac remodelling is angiotensin (Ang) II. 2. In the present study, the suppression subtractive hybridization method was used to identify differentially expressed cDNAs in adult rat cardiac fibroblasts induced by AngII. 3. Following mRNA isolation of non-stimulated and AngII-stimulated cells, cDNAs of both populations were prepared and subtracted by suppression polymerase chain reaction. Sequencing of the partially enriched cDNAs identified 36 genes differentially expressed, including ECM proteins (pro-alpha(1) collagen type III, fibronectin), structural protein (spectrin), enzyme (GTP-specific succinyl-CoA synthetase), transcriptional regulators (glucocorticoid-induced leucine zipper, inhibitor of DNA binding 3) and proteins involved in cell division control (cdc2) or cell signalling (insulin-like growth factor binding protein-3, mutant p53-binding protein, grp75, CGI-121, protein phosphatase type 2A, tspan-2 and Sam68). 4. The diversity of genes identified in the present study further emphasises the central role of AngII in the regulation of cardiac remodelling.
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PMID:Identification of differentially expressed genes induced by angiotensin II in rat cardiac fibroblasts. 1644 97

The WD repeat scaffolding protein RACK1 can mediate integration of the insulin-like growth factor I receptor (IGF-IR) and integrin signaling in transformed cells. To address the mechanism of RACK1 function, we searched for regulatory proteins that associate with RACK1 in an IGF-I-dependent manner. The serine threonine phosphatase protein phosphatase 2A (PP2A) was found associated with RACK1 in serum-starved cells, and it dissociated immediately upon stimulation with IGF-I. This dissociation of PP2A from RACK1 and an IGF-I-mediated decrease in cellular PP2A activity did not occur in cells expressing either the serine 1248 or tyrosine 1250/1251 mutants of the IGF-IR that do not interact with RACK1. Recombinant RACK1 could bind to PP2A in vitro and restore phosphatase activity to PP2A from IGF-I-stimulated cells. Ligation of integrins with fibronectin or Matrigel was sufficient to facilitate IGF-I-mediated dissociation of PP2A from RACK1 and also to recruit beta1 integrin as PP2A dissociated. By using TAT-fused N-terminal and C-terminal deletion mutants of RACK1, we determined that both PP2A and beta1 integrin interact in the C terminus of RACK1 within WD repeats 4 to 7. This suggests that integrin ligation displaces PP2A from RACK1. MCF-7 cells overexpressing RACK1 exhibited enhanced motility, which could be reversed by the PP2A inhibitor okadaic acid. Small interfering RNA-mediated suppression of RACK1 also decreased the migratory capacity of DU145 cells. Taken together, our findings indicate that RACK1 enhances IGF-I-mediated cell migration through its ability to exclusively associate with either beta1 integrin or PP2A in a complex at the IGF-IR.
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PMID:Insulin-like growth factor I controls a mutually exclusive association of RACK1 with protein phosphatase 2A and beta1 integrin to promote cell migration. 1670 58

The human P zero-related protein (hPZR) has a unique function in regulating cell migration. This activity is dependent on both its cytoplasmic immunoreceptor tyrosine inhibitory motif (ITIM) and its interaction with the tyrosine protein phosphatase, src homology phosphatase-2 (SHP-2). Here, using in silico and cDNA cloning approaches, we identify the murine ITIM-containing hPZR ortholog, mPZR, together with its ITIM-less isoform, mPZRb. We demonstrate that, like hPZR, these type 1 integral murine transmembrane isoforms are derived by differential splicing from a single gene transcription unit on mouse chromosome 1, and differ only in the sequence of their cytoplasmic domains. Importantly, mPZR mimicks hPZR functionally by accelerating SHP-2-mediated cell migration on fibronectin. Interestingly, we further demonstrate that although neither mPZR nor mPZRb is expressed in murine pluripotent embryonic stem cells, they first appear at approximately day 3 of blastocyst formation in vivo and of embryoid body formation in vitro. These studies thus provide the basis for defining the function of the mPZR isoforms in vivo, particularly with respect to their roles in regulating SHP-2-dependent cell migration during development.
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PMID:The murine ortholog of the SHP-2 binding molecule, PZR accelerates cell migration on fibronectin and is expressed in early embryo formation. 1744 Sep 60


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