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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon maturation, primary rat oligodendrocytes become resistant to coronavirus JHM (JHMV) infection at an early stage. Involvement of cAMP-dependent protein kinase (PK) in the regulation of oligodendrocyte differentiation has been established (S. Beushausen et al. (1987). J. Virol. 61, 3795-3803). An inducer which accelerates maturation, dibutyryl cyclic AMP (dbcAMP) also upregulates the expression of the regulatory subunit, R1 of PK1. Since (i) early block preventing infection of mature oligodendrocytes can be bypassed when transfection with genomic RNA is used and (ii) inhibitors of PKs counteract the dbcAMP effect, so as to alleviate the inhibition of JHMV, enhanced expression of R1 appeared to be connected with virus restriction. This idea was confirmed following upregulation of the R1 gene in fully permissive L-2 cells. There was a connection between an effect due to R1 and dephosphorylation of the nucleocapsid protein N by an endosomal phosphoprotein phosphatase (PPPase) having the properties of types 1 or 2A enzyme which occurs during penetration of inoculum virions. An inhibition in vitro (cell free) of N dephosphorylation by R1 together with evidence that in vivo (cell culture) overexpression of R1 inhibited the endosomal PPPase as well as replication of JHMV supports the hypothesis that uncoating of the JHMV inoculum occurs after dephosphorylation, a step obligatory for dissociation of the N protein from the genome. Thus inhibition by R prevents uncoating and thereby interferes with the commencement of replication. These observations intimate the existence of a novel mechanism controlling a virus infection of specific cell target(s) undergoing a process of differentiation and maturation in the central nervous system.
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PMID:Regulation of the initiation of coronavirus JHM infection in primary oligodendrocytes and L-2 fibroblasts. 891 31

Angiotensin II (Ang II) induces hypertrophy of cultured proximal tubular epithelial cells including the LLC-PK1 cell line. We have previously shown that this hypertrophy appears in the G1-phase of the cell cycle. Since progression through the cell cycle is controlled by a series of cyclin and cyclin-dependent kinase (CdK) complexes that may be inactivated by CdK inhibitors, we studied the expression of the CdK-inhibitor p27Kip1 in LLC-PK1 cells challenged with Ang II. Compared to cells grown in serum-free medium, Ang II treatment enhanced p27Kip1 protein, but not mRNA expression. This p27Kip1 induction was mediated through AT1-receptors. Exogenous TGF-beta also stimulated p27Kip1 protein expression. Immunoprecipitation experiments revealed that p27Kip1 preferentially associated with CdK4 in Ang II-treated LLC-PK1 cells and that the activity of this kinase was inhibited after Ang II-treatment, an effect that may be generated by increased p27Kip1 binding to cyclin D1-CdK4 complexes. In contrast, p27Kip1 was not associated with cyclin E-CdK2 complexes in Ang II-stimulated cells. Treatment of LLC-PK1 cells with p27Kip1 antisense, but not missense, oligonucleotides abolished the Ang II-mediated cell hypertrophy as measured by de novo protein synthesis and total protein content, and facilitated entry into the S-phase of the cell cycle. Our findings suggest that Ang II stimulates p27Kip1 expression in renal cells. Furthermore, this induction of the CdK-inhibitor appears pivotal in the hypertrophy induced by Ang II and elucidates the molecular mechanisms associated with this growth response in proximal tubular cells.
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PMID:Angiotensin II-stimulated hypertrophy of LLC-PK1 cells depends on the induction of the cyclin-dependent kinase inhibitor p27Kip1. 894 98

Urokinase-type plasminogen activator (uPA) expression is induced upon cytoskeletal reorganization (CSR) by a mechanism independent of protein kinase C and cAMP protein kinase in nontransformed renal epithelial (LLC-PK1) cells. This CSR-dependent uPA gene activation is mediated by an AP-1-recognizing element located 2 kilobases upstream of the transcription initiation site. The phosphorylation of c-Jun, a component of AP-1, is induced by CSR, which seems to increase both the activity and stability of c-Jun (Lee, J. S., von der Ahe, D., Kiefer, B., and Nagamine, Y. (1993) Nucleic Acids Res. 21, 3365-3372). It has been shown that c-Jun is phosphorylated by members of the mitogen-activated protein kinase family, i.e. ERKs and JNKs. ERKs are activated through a growth factor-coupled Ras/Raf-dependent signaling pathway, while JNKs are activated through a stress-induced signaling pathway. Although CSR induces both ERK-2 and JNK activity, JNK does not seem to be involved in the uPA gene induction because UV irradiation, which activates JNK as efficiently as CSR, does not activate the uPA promoter. Further analysis showed the involvement of SOS, Ras, and Raf-1 in the pathway induced by CSR. Our results suggest that cells sense changes in cell morphology using the cytoskeleton as a sensor and respond by activating the ERK-involving signaling pathway from within the cell.
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PMID:Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. 899 79

NHE3 is the Na+/H+ exchanger located on the intestinal and renal brush border membrane, where it functions in transepithelial Na+ absorption. The brush border Na+ absorptive process is acutely inhibited by activation of cAMP-dependent protein kinase, but the molecular mechanism of this inhibitory effect is poorly understood. We have identified two regulatory proteins, E3KARP and NHERF, that interact with NHE3 to enable cAMP to inhibit NHE3. The two regulatory proteins are structurally related, sharing approximately 50% identity in amino acid sequences. It has been previously shown that when NHE3 is transfected into PS120 fibroblasts or Caco-2 cells, cAMP failed to inhibit NHE3 activity. Northern blot analysis showed that both PS120 and Caco-2 cells lacked the expression of both E3KARP and NHERF. In contrast, other cell lines in which cAMP inhibits NHE3, including OK, CHO, and LLC-PK1 cells, expressed NHERF-related regulatory proteins. To determine their functions in cAMP-dependent inhibition of NHE3, E3KARP and NHERF were transfected into PS120/NHE3 fibroblasts. Transfection in PS120/NHE3 fibroblasts with either NHERF or E3KARP reconstituted cAMP-induced inhibition of NHE3, resulting in 25-30% inhibition in these cells.
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PMID:cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. 909 37

The protooncogene G alpha(i-2) plays a pivotal role in signaling pathways that control renal cell growth and differentiation. Mitogen-activated protein kinases (MAPKs) are potential downstream effectors for G alpha(i-2) in these pathways. In predifferentiated LLC-PK1 renal cells, the temporal maximal expression of G alpha(i-2) coincided with maximal activation of MAPK(p42/p44). By contrast, pertussis toxin treatment of these cells inhibited cell growth and reduced MAPK(p42/p44) activity by 30%. These findings reflected upstream activation of MAPK kinase (MEK1), as transient transfection of cells with a plasmid encoding a constitutively active form of MEK1 increased MAPK(p42/p44) activity and cell growth, whereas treatment with PD-098059, an inhibitor of MEK1 activity, reduced MAPK(p42/p44) activity and cell growth. Expression of a guanosinetriphosphatase (GTPase)-deficient G alpha(i-2) in these cells increased MAPK(p42/p44) activity and correspondingly reduced cell doubling time from 24 to 10 h without altering the activity of Raf-1 or c-Jun/stress-activated protein kinases (SAPKs). By contrast, expression of a GTPase-deficient G alpha(i-3) in these cells reduced both their cell doubling time by 30% and MAPK(p42/p44) activity by 60%. As the known MEKK isoforms (MEKK1, -2, and -3) can also activate SAPKs, these findings suggest the GTP-charged G alpha(i-2) subunit transduces growth signals in renal cells via activation of MAPK(p42/p44) and that such activation may be linked to pathways containing novel MEKK isoforms that preferentially activate MEKs.
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PMID:G alpha(i-2) mediates renal LLC-PK1 growth by a Raf-independent activation of p42/p44 MAP kinase. 912 7

The aquaporin-2 (AQP2) vasopressin water channel is translocated to the apical membrane upon vasopressin stimulation. Phosphorylation of serine 256 of AQP2 by cAMP-dependent protein kinase has been shown, but its relation to vasopressin-regulated translocation has not been elucidated. To address this question, wild type (WT) AQP2 and a mutant with alanine in place of serine 256 of AQP2 (S256A) were expressed in LLC-PK1 cells by electroporation. Measurements by a stopped-flow light-scattering method revealed that the osmotic water permeability (Pf) of LLC-PK1 cells transfected with WT was 69.6 +/- 6.5 microm/s (24.8 +/- 2.2 microm/s for mock-transfected), and stimulation by 500 microM 8-(4-chlorophenylthio)-cAMP increased the Pf by 85 +/- 12%. When S256A AQP2 was transfected, the cAMP-dependent increase in the Pf was only 8 +/- 5%. After cAMP stimulation, the increase in surface expression of AQP2 determined by surface biotin labeling was 4 +/- 10%, significantly less than that for WT (88 +/- 5%). In addition, an in vivo [32P]orthophosphate labeling assay demonstrated significant phosphorylation of WT AQP2 and only minimal phosphorylation of S256A AQP2 in LLC-PK1 cells. Our results indicated that serine 256 of AQP2 is necessary for regulatory exocytosis and that cAMP-responsive redistribution of AQP2 may be regulated by phosphorylation of AQP2.
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PMID:Phosphorylation of serine 256 is required for cAMP-dependent regulatory exocytosis of the aquaporin-2 water channel. 916 47

Vasopressin-dependent translocation of aquaporin-2 (AQP2) between intracellular vesicles and the plasma membrane has been demonstrated in vivo and in vitro. Furthermore, the vasopressin-induced increase in apical membrane water permeability of renal principal cells is dependent on a rise in intracellular adenosine 3',5'-cyclic monophosphate and activation of protein kinase A (PKA). To determine whether trafficking of AQP2 is dependent on PKA phosphorylation, we first examined the effect of the PKA-inhibitor N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89) on AQP2 translocation in transfected LLC-PK1 cells. Vasopressin-induced membrane insertion of AQP2 was completely inhibited by pretreatment of the cells for 60 min with H-89. This reagent also caused a dense accumulation of AQP2 in the Golgi region. Next, LLC-PK1 cells were stably transfected with AQP2 cDNA in which the PKA phosphorylation site, Ser256, was replaced with alanine (S256A). S256A-AQP2 was not phosphorylated in vitro by PKA, and S256A-AQP2 was mainly localized to intracellular vesicles in the basal condition, similar to wild-type AQP2. However, after stimulation with vasopressin or forskolin, the cellular distribution of S256A-AQP2 remained unchanged. In addition, the usual vasopressin-induced increase in endocytosis seen in AQP2-transfected cells was not observed in S256A-AQP2-transfected cells. These results demonstrate that the Ser256 PKA phosphorylation site is possibly involved in the vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis.
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PMID:Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. 922 44

Parathyroid hormone (PTH) activates multiple intracellular effectors, including adenylyl cyclase (AC) and phospholipase C (PLC), via a single receptor [PTH/parathyroid hormone-related protein receptor (PTHR)] expressed in bone and kidney. Homologous desensitization of PTHR signaling occurs, but the relative importance of reduced receptor expression vs. impaired receptor-effector coupling in this process remains unclear. It also is not known if AC and PLC responses to PTH are desensitized independently or interdependently. In LLC-PK1 cells that expressed transfected wild-type PTHRs, PTH caused dose- and time-dependent desensitization of both the AC and PLC-responses to PTH without altering PTHR expression. Desensitization of AC was blocked in mutant cells resistant to adenosine 3',5'-cyclic monophosphate but not when cells expressed mutant PTHRs with defective PLC coupling. Desensitization of PLC was unaffected by PKA blockade, partially mimicked by phorbol ester, and not reproduced by agents that selectively activated AC. The finding that homologous PTHR desensitization in LLC-PK1 cells is signal specific suggests that prior exposure of other cells to PTH also may induce discordant regulation of subsequent PTHR signaling, altering the character as well as the intensity of the hormonal response.
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PMID:Mechanisms of homologous and heterologous desensitization of PTH/PTHrP receptor signaling in LLC-PK1 cells. 927 93

Intracellular signal transduction for regulation of alkaline phosphatase (ALP) activity in renal epithelial cells treated with calcitonin is not yet completely understood, although it is known that calcitonin receptors couple to cyclic AMP-dependent protein kinase (PKA) and calcium/phospholipid-dependent protein kinase (PKC). Salmon calcitonin increased the cyclic AMP content in LLC-PK1 porcine kidney cells in a concentration-dependent manner. When the confluent cells were incubated for 47 h after a 1 h-pulse exposure or continuously exposed to calcitonin and forskolin for 48 h, ALP activity in the cells was increased by calcitonin about 2-fold compared with the basal activity at the maximum level but was not dependent on the exposure time; it was markedly increased by forskolin in parallel with the exposure time. The increase in activity produced by calcitonin was abolished by a PKA inhibitor H-89, and, in contrast, potentiated by a PKC inhibitor, NA-382 to near the forskolin-induced level. These results indicate that calcitonin exerts a dual-regulation of ALP activity in LLC-PK1 cells, positively through the PKA pathway and negatively through PKC.
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PMID:Dual regulation of alkaline phosphatase activity by calcitonin in porcine kidney cells. 944 8

The glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) bind similar ligands and target genes in vitro yet have distinct roles in vivo. With a single exception, known mechanisms conferring specificity have been limited to prereceptor mechanisms. These alone cannot account for specificity, particularly at a transcriptional level. These studies aimed to determine whether receptor-specific transcriptional regulation via physiological modulators of cellular signaling pathways, and MR-, as well as GR-specific interactions, could be demonstrated. By comparing modulation of GR- and MR-mediated transactivation in renal LLC-PK1 cells, we have identified several activators of intracellular signaling pathways that discriminate between the GR and the MR and demonstrate that differential regulation occurs at relatively specific points in the signaling pathway. The phosphatase inhibitor, okadaic acid, and the protein kinase G activator, sodium nitroprusside, stimulate only GR-mediated transactivation, in contrast to modulators of other protein kinase pathways that act in parallel on both receptors. The GR-specific effect of okadaic acid is observed only at doses where both phosphatases 1 and 2A are inhibited. MR-specific modulators include a centrally active alpha-2 adrenergic agonist and the thyroid receptor. Comparison of the interaction between the thyroid receptor and the GR, or the MR, distinguish two types of repression, only one of which is receptor-specific. These studies identify several signal transduction pathways that can differentially activate either the MR or the GR at a transcriptional level and might play physiological roles in conferring MR- or GR-specific regulation.
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PMID:Intracellular signaling pathways confer specificity of transactivation by mineralocorticoid and glucocorticoid receptors. 952 46


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