Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P67775 (alpha isoform)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been previously shown that 5-HT uptake inhibition produced by tetanus toxin (TeTx) corresponds to a non-competitive inhibition, and it is preceded by phosphorylation of the tyrosine-kinase receptor trkA, phospholipase C activation and translocation of protein kinase C isoforms [FEBS Lett. 481 (2000) 177; FEBS Lett. 486 (2000) 136]. In the present work, it is shown that agonists of tyrosine-kinase receptors (NGF, EGF, basic FGF) enhance Na(+)-dependent, 5-hydroxytryptamine (serotonin, 5-HT) uptake in the synaptosomal-enriched P(2) fraction from rat-brain, suggesting a divergence in the intracellular signal pathways triggered by TeTx and by agonists of TyrK receptors. Co-applications of TeTx and agonists of TyrK receptors result in a mutual and partial reversion of their effects on 5-HT transport. In spite of their differences on transport, TeTx, TPA and NGF produce an increase in serotonin transporter phosphorylation in Ser separately, which is abolished by the PKC-inhibitor bisindolylmaleimide-1. Co-application of sodium vanadate, a tyrosine-phosphatase inhibitor, partially abolishes the effect produced by TeTx, whereas genistein, a tyrosine-kinase inhibitor, does not exert any variation of TeTx inhibition. Analyses by immunoblotting of the activation of specific PKC isoforms activation, determined as translocation to the membrane compartment, reveals differences in the pattern produced by NGF and TeTx. PKC gamma, delta, and epsilon isoforms are equally activated by both compounds, whereas the beta isoform is activated in a sustained manner only by TeTx, and the alpha isoform is only down-regulated by NGF. The aim of the present work was to explore whether NGF have the same effect on 5-HT transport than TeTx, since both compounds share the ability of activate part of the same transduction pathways. In spite of this, growth factors and TeTx show an opposite effect on 5-HT transport, even though SERT phosphorylation is enhanced in both cases. The differential effect on alpha- and beta-PKC isoenzymes found between NGF and TeTx action could explain this apparent discrepancy.
 ...
PMID:Serotonin transport is modulated differently by tetanus toxin and growth factors. 1259 Sep 35

Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.
 ...
PMID:Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. 1263 47

In Saccharomyces cerevisiae, the Tor proteins mediate a wide spectrum of growth-related cellular processes in response to nutrients. The pleiotropic role of the Tor proteins is mediated, at least in part, by type 2A protein phosphatases (PP2A) and 2A-like protein phosphatases. Tor-mediated signaling activity promotes the interaction of phosphatase-interacting protein Tap42 with PP2A and 2A-like protein phosphatases. The distinct complexes formed between Tap42 and different phosphatases mediate various cellular events and modulate phosphorylation levels of many downstream factors in the Tor pathway in a Tor-dependent and rapamycin-sensitive manner. In this study, we demonstrate that the interaction between Tap42 and the catalytic subunits of PP2A (PP2Ac) is required for cell cycle-dependent distribution of actin. We show that mutations in PP2Ac and Tap42 that perturb the interaction cause random distribution of actin during the cell cycle and that overexpression of the Rho2 GTPase suppresses the actin defects associated with the mutants. Our findings suggest that the Tap42-PP2Ac complex regulates the actin cytoskeleton via a Rho GTPase-dependent mechanism. In addition, we provide evidence that PP2A activity plays a negative role in controlling the actin cytoskeleton and, possibly, in regulation of the G(2)/M transition of the cell cycle.
 ...
PMID:The Tap42-protein phosphatase type 2A catalytic subunit complex is required for cell cycle-dependent distribution of actin in yeast. 1269 13

Calcineurin is an important signaling molecule in mesangial cells in vitro and is involved in some manifestations of diabetic nephropathy in vivo. However, calcineurin acts in a cell-specific and tissue-specific manner in the kidney, and mechanisms of specificity are unknown. Three closely related isoforms of the calcineurin A (CnA) subunit are expressed in a tissue-specific manner. This study was undertaken to determine if specificity of calcineurin action is linked to regulation of CnA isoforms in the diabetic kidney. After induction of diabetes with streptozotocin, expression of all three CnA isoforms rapidly increased, primarily in the thick ascending limb of Henle (TAL). After prolonged diabetes, increase specifically of the alpha isoform was observed in collecting ducts (CD) and in endothelial cells of glomeruli. Aquaporin 2 (AQP2), a putative substrate of calcineurin phosphatase in the kidney, is also involved in diabetic nephropathy. Co-localization of CnA isoforms with AQP2 revealed that CnA-alpha is the predominant isoform that associates with AQP2 in the diabetic kidney. Furthermore, inhibition of calcineurin with cyclosporin A (CsA) alters AQP2 localization and phosphorylation in principal cells of CD. Alterations in subcellular localization of AQP2 were parallel with CnA-alpha. Similarly, CsA treatment results in a further increase in urine output compared with diabetes alone, suggesting a functional consequence of inhibiting calcineurin-mediated regulation of AQP2. In conclusion, all three isoforms of CnA are upregulated in the diabetic kidney. Increased expression of CnA-alpha, in particular, is observed in glomeruli and CD and participates in regulation of AQP2 expression, phosphorylation, and function.
 ...
PMID:Differential expression of calcineurin A isoforms in the diabetic kidney. 1515 53

We have recently shown that in colon cancer cells, Vitamin D receptor (VDR) interacts with the catalytic subunit of Ser/Thr protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. The VDR-PP1c and VDR-PP2Ac interactions were ligand independent in vivo, and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-mediated increase in VDR-associated phosphatase activity resulted in dephosphorylation and inactivation of p70S6 kinase in colon cancer cells. Here, we demonstrate that in myeloid leukemia cells, 1,25(OH)(2)D(3) treatment increased the Thr389 phosphorylation of p70S6 kinase. Accordingly, 1,25(OH)(2)D(3) decreased VDR-associated Ser/Thr protein phosphatase activity by dissociating VDR-PP1c and VDR-PP2Ac interactions. Further, 1,25(OH)(2)D(3) increased the association between VDR and Thr389 phosphorylated p70S6 kinase. Finally, by using non-secosteroidal VDR ligands, we demonstrate a separation between transactivation and p70S6 kinase phosphorylation activities of VDR and show pharmacologically that p70S6 kinase phosphorylation correlates with HL-60 cell differentiation.
 ...
PMID:Ligand modulates VDR-Ser/Thr protein phosphatase interaction and p70S6 kinase phosphorylation in a cell-context-dependent manner. 1522 71

Phosphotyrosyl phosphatase activator PTPA is a type 2A phosphatase regulatory protein that possesses an ability to stimulate the phosphotyrosyl phosphatase activity of PP2A in vitro. In yeast Saccharomyces cerevisiae, PTPA is encoded by two related genes, RRD1 and RRD2, whose products are 38 and 37% identical, respectively, to the mammalian PTPA. Inactivation of either gene renders yeast cells rapamycin resistant. In this study, we investigate the mechanism underling rapamycin resistance associated with inactivation of PTPA in yeast. We show that the yeast PTPA is an integral part of the Tap42-phosphatase complexes that act downstream of the Tor proteins, the target of rapamycin. We demonstrate a specific interaction of Rrd1 with the Tap42-Sit4 complex and that of Rrd2 with the Tap42-PP2Ac complex. A small portion of PTPA also is found to be associated with the AC dimeric core of PP2A, but the amount is significantly less than that associated with the Tap42-containing complexes. In addition, our results show that the association of PTPA with Tap42-phosphatase complexes is rapamycin sensitive, and importantly, that rapamycin treatment results in release of the PTPA-phosphatase dimer as a functional phosphatase unit.
 ...
PMID:The yeast phosphotyrosyl phosphatase activator is part of the Tap42-phosphatase complexes. 1568 91

Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long-term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium-calmodulin-dependent protein kinase II (CaMKIIalpha) at Thr286, a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIalpha or other synaptic proteins. Dopamine depletion decreased CaMKIIalpha levels in postsynaptic density-enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP-32 phosphorylation at Thr34, but increased DARPP-32 phosphorylation at Thr75. Levodopa administration reversed the increased phosphorylation of both CaMKIIalpha and DARPP-32. Normal ageing increased the levels of PP1(gamma1 isoform) but decreased levels of the PP1gamma1-targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIalpha and DARPP-32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII-PP1 substrate, Ser831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9-20 months) dopamine depletion. Interaction of ageing-related changes in PP1 with the dopamine depletion-induced changes in CaMKIIalpha may account for enhanced GluR1 phosphorylation only after long-term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side-effects associated with dopamine replacement therapy.
 ...
PMID:Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism. 1602 14

Protein phosphatase 2A (PP2A) contains a 36-kDa catalytic subunit (PP2Ac), a 65-kDa structural subunit (PR65/A), and a regulatory B subunit. The core enzyme consists of the structural and catalytic subunits. The catalytic subunit exists as two closely related isoforms, alpha and beta. Several natural toxins, including okadaic acid (OA) and microcystins, specifically inhibit PP2A. To obtain biologically active recombinant PP2A and to compare the properties of the PP2A catalytic subunit alpha and beta isoforms, we expressed human PP2Acalpha and cbeta in High Five insect cells. The recombinant PP2Acalpha and cbeta possess similar phosphatase activities using p-NPP and phosphopeptide as substrates and are strongly inhibited by OA and microcystin-LR to similar degrees. In addition, PP2Acalpha or cbeta was co-expressed with PR65/A and co-purified as a core dimer, PP2AD (Aalpha/calpha and Aalpha/cbeta) with PR65alpha/Aalpha. The recombinant PP2AD bound to the B subunit in vitro. These results show that the recombinant PP2Acalpha and cbeta are identical in their ability to associate with the A and B subunits, in their phosphatase activities, and in carboxyl-methylation. Furthermore, our results show that High Five insect cells can produce biologically active recombinant PP2A, which should be a valuable tool for detecting natural toxins and investigating the mechanism of PP2A catalysis and other protein interactions.
 ...
PMID:Baculovirus expression, purification, and characterization of human protein phosphatase 2A catalytic subunits alpha and beta. 1603 40

Inositol polyphosphate phosphatases and phosphoinositides second messengers have been associated with major cellular functions as growth, differentiation, apoptosis, protein trafficking and motility. To characterize the role of inositol phosphatases in cell physiology, we have isolated the mouse Inositol polyphosphate 4-phosphatase type II (Inpp4b) cDNA. The murine Inpp4b locus was mapped on chromosome 8 in a synthenic region of the human 4q27-31 interval between Il-15 and Usp38. The mouse Inpp4b proteins, alpha and beta isoforms, encoded by this locus contained 927 and 941 amino acids respectively with a consensus phosphatase catalytic site and a conserved C2 domain that are highly similar with the human and rat homologues. Interestingly, we characterized a novel shorter isoform of Inpp4balpha resulting from an alternative translation initiation site and exon 5 skipping. Inpp4b C2 domain interacted with preferential affinity to phosphatidic acid and phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P(3)) lipids. While analysis of Inpp4b transcript and protein expression demonstrated a broad tissue distribution for the alpha isoform, as for the paralogue Inpp4aalpha and beta isoforms, it also displayed a limited hematopoietic lineage distribution whereas the Inpp4bbeta isoform had a highly restricted pattern. Importantly, the Inpp4bbeta localized to the Golgi apparatus whereas Inpp4balpha was mainly cytosolic, suggesting a different cellular function for this isoform. Together our characterization of the murine Inpp4b gene expression pattern, cellular sublocalization and interacting lipids support highly specific function for individual Inpp4 phosphatase proteins.
 ...
PMID:Characterization of the murine Inpp4b gene and identification of a novel isoform. 1663 25

Emerging evidence suggests critical roles for protein phosphatase 2A (PP2A) in islet beta cell function, including survival and demise (Kowluru A: Biochemical Pharmacol 69:1681-1691, 2005). Herein, we identified an okadaic acid (OKA)-sensitive PP2A-like phosphatase in the nuclear fraction from insulin-secreting INS-1 cells. Western blot analysis indicated relatively higher abundance of the catalytic subunit of protein phosphatase 4 (PP4c) compared to PP2Ac in this fraction. Autoradiographic and vapor-phase equilibration analyses suggested that the nuclear PP4c undergoes OKA-sensitive carboxylmethylation (CML) when S-adenosyl-L-((3)H-methyl) methionine (SAM) was used as the methyl donor. Exposure of INS cells to interleukin-1beta (IL-1beta; 600 pM; 48 h) resulted in a marked increase in nitric oxide (NO) release with concomitant reduction in the degree of expression, the CML and the catalytic activity of only PP4, but not PP2A, in the nuclear fraction. Immunoprecipitation studies suggested potential complexation of PP4c with nuclear lamin-B, a key regulatory protein involved in the nuclear envelope assembly. Based on these findings, we propose that IL-1beta-mediated inhibition of PP4 activity might result in the retention of lamin-B in its phosphorylated state, which is a requisite for its degradation by caspases leading to the apoptotic demise of the beta cell (Veluthakal et al.: Am J Physiol Cell Physiol 287:C1152-C1162, 2004).
 ...
PMID:Localization of a nuclear serine/threonine protein phosphatase in insulin-secreting INS-1 cells: potential regulation by IL-1beta. 1683 Feb 32


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