Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the glomerular mesangial cell, platelet-derived growth factor (PDGF) activates several signal transduction pathways. We examined the effect of PDGF on cAMP production and on cAMP-dependent protein kinase (A-kinase) activation. In mesangial cells, PDGF stimulated cAMP production in a dose- and time-dependent manner. This effect of PDGF was not prevented by pre-incubation with 50 microM indomethicin. PDGF also activated type I A-kinase, the predominate A-kinase isoform in mesangial cells, measured either by a decrease in A-kinase photoaffinity labeling with 8-azido-[32P]-cAMP, or by an increase in A-kinase substrate phosphorylation. The activation of A-kinase by PDGF is not dependent on the intermediate production of prostaglandins or cGMP. These data suggest that A-kinase participates in PDGF-induced signaling events in mesangial cells.
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PMID:Type I A-kinase is activated by platelet-derived growth factor in mesangial cells. 860 27

To study the role of mitogen-activated protein kinase in the regulation of M2 receptors, we studied the effect of platelet-derived growth factor (PDGF) on M2 receptor gene expression. PDGF (4 ng/ml) caused a time-dependent decrease in M2 receptor number and in m2 receptor mRNA levels in HEL 299 cells. The PDGF-induced loss in m2 mRNA required de novo protein synthesis and occurred through a decrease in the rate of transcription of the m2 receptor gene. The down-regulation of M2 receptors was not accompanied by an uncoupling of the remaining receptors, indicating a large receptor reserve in these cells. Preincubations with the phosphatidylinositol 3-kinase inhibitor wortmannin, the protein kinase C inhibitor GF 109203X and the cAMP-dependent protein kinase inhibitor H-8 did not attenuate PDGF-induced down-regulation, indicating a lack of involvement of these enzymes in the down-regulation process. Activation of the extracellular signal-regulated protein kinase (ERK) 1 and 2 proteins was measured by an "in gel" phosphorylation assay. Carbachol did not activate ERK1 or 2, whereas PDGF and 4 beta-phorbol 13,14-dibutyrate resulted in a large increase in ERK1 and 2 activity along with a decrease in m2 mRNA. Preincubation with PD 098059, an inhibitor of mitogen-activated protein kinase kinase, inhibited PDGF- and 4 beta-phorbol 13,14-dibutyrate-mediated activation of ERK 1 and 2 in a concentration-dependent manner. The inhibitory action of PD 098059 was reflected at the mRNA level attenuating both PDGF- and 4 beta-phorbol 13,14-dibutyrate-mediated decreases in m2 mRNA. These results suggest a role of ERK1 and 2 in the regulation of muscarinic m2 receptor gene expression.
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PMID:Regulation of m2 muscarinic receptor gene expression by platelet-derived growth factor: involvement of extracellular signal-regulated protein kinases in the down-regulation process. 941 6

There is growing evidence that pentoxifylline (PTX) may have potential value as an antiproliferative and antifibrogenic agent. To assess whether this drug may be of use in the prevention of atherosclerosis or restenosis after angioplasty, we investigated the ability of PTX to inhibit proliferation and collagen synthesis in rat vascular smooth muscle cells (VSMCs) under both basal and platelet-derived growth factor (PDGF)- or transforming growth factor-beta (TGF-beta)- stimulated conditions. Intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in confluent cells using enzyme immunoassay kits. Cell proliferation was measured by methyltetrazolium assay. Cell cycle distribution was determined by flow cytometry. Total collagen synthesis was measured by 3H-proline incorporation assay. Expression of collagen alpha 1(I) and collagen alpha 1(III) mRNAs was detected by northern blotting. Addition of PTX to VSMC cultures suppressed both basal and PDGF-AB (25 ng/ml)-driven cell proliferation, in conjunction with a cell cycle blockade at the G1/S phase at 24 h. This effect was predominantly cAMP-dependent, as PTX increased cAMP in a dose-dependent manner (0.03 to 0.33 mg/ml) but not cGMP level, and the addition of dibutyryl-cAMP (0.2 to 2 m m) closely mimicked the effect of PTX. Furthermore, co-incubation with a selective inhibitor of cAMP-dependent protein kinase (PKA), H-89 (2.0 microm), or an N -myristoylated PKA pseudosubstrate nonapeptide, m-phi PKA (10 microm), prevented the antimitogenic effect of PTX. PTX also suppressed both basal and TGF- beta 1-augmented collagen alpha 1(I) and collagen alpha 1(III) mRNA levels beginning at 24 h, and attenuated both basal and TGF-beta 1 (5 ng/ml)-stimulated total collagen synthesis at 48 h. Co-incubation with H-89 or m-phi PKA reversed PTX-attenuated collagen alpha 1(I) and collagen alpha 1(III) mRNA levels at 24 h. These data suggest that the antimotigenic and anticollagen effects of PTX were mediated predominantly through a cAMP-PKA effector pathway. The dual effect of PTX on VSMC proliferation and collagen synthesis may form the rationale for animal or clinical trials for the treatment of vascular occlusion due to atherosclerosis and restenosis following angioplasty.
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PMID:Pentoxifylline inhibits PDGF-induced proliferation of and TGF-beta-stimulated collagen synthesis by vascular smooth muscle cells. 1032 5

Growth factor receptors provide a major mechanism for the activation of the nonreceptor tyrosine kinase c-Src, and this kinase in turn up-regulates the activity of N-methyl-D-aspartate (NMDA) receptors in CA1 hippocampal neurons (1). Unexpectedly, applications of platelet-derived growth factor (PDGF)-BB to cultured and isolated CA1 hippocampal neurons depressed NMDA-evoked currents. The PDGF-induced depression was blocked by a PDGF-selective tyrosine kinase inhibitor, by a selective inhibitor of phospholipase C-gamma, and by blocking the intracellular release of Ca(2+). Inhibitors of cAMP-dependent protein kinase (PKA) also eliminated the PDGF-induced depression, whereas a phosphodiesterase inhibitor enhanced it. The NMDA receptor-mediated component of excitatory synaptic currents was also inhibited by PDGF, and this inhibition was prevented by co-application of a PKA inhibitor. Src inhibitors also prevented this depression. In recordings from inside-out patches, the catalytic fragment of PKA did not itself alter NMDA single channel activity, but it blocked the up-regulation of these channels by a Src activator peptide. Thus, PDGF receptors depress NMDA channels through a Ca(2+)- and PKA-dependent inhibition of their modulation by c-Src.
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PMID:Platelet-derived growth factor receptor-induced feed-forward inhibition of excitatory transmission between hippocampal pyramidal neurons. 1052 46

Modulation of cell proliferation has often been thought to be connected to changes in the activity of pH-regulatory transporters and consequently intracellular pH (pH(i)). The influence of natriuretic peptides, diadenosine polyphosphates, adenosine and ATP as well as platelet-derived growth factor (PDGF) on pH(i) regulation of cultured rat mesangial cells was examined with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The inhibitors of Na(+)/H(+) exchange, amiloride and HOE694, blocked pH(i) recovery completely in the absence of and by approximately 50% in the presence of HCO(3)(-)/CO(2). Natriuretic peptides (ANP, BNP, CNP, urodilatin) completely inhibited pH(i) recovery in the absence of and by approximately 40% in the presence of HCO(3)(-)/CO(2). These effects were abolished by the cGMP-dependent protein kinase inhibitor KT5823. Diadenosine polyphosphates (Ap3A-Ap6A), ATP and adenosine also inhibited pH(i) recovery completely in the absence of and partially (30-40%) in the presence of HCO(3)(-)/ CO(2). The effect of adenosine was abolished in the presence of the cAMP-dependent protein kinase inhibitor KT5720, and that of Ap5A by the protein kinase C inhibitor calphostin C. PDGF activated acid extrusion in these cells by approximately 40%. From the four cloned isoforms of the Na(+)/H(+) exchanger in the rat, only transcripts of NHE-1 were found in these mesangial cell cultures using RT-PCR analysis. These data suggest that in these rat mesangial cells the Na(+)/H(+) exchanger, specifically the NHE-1 isoform, accounts for around 50% of pH(i) recovery from an acid load under physiological conditions, and that Na(+)/H(+) exchange stimulated by acidification can be inhibited by activation of PKG, PKA, and PKC and stimulated by PDGF after acute exposition to these agonists.
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PMID:Natriuretic peptides and diadenosine polyphosphates modulate pH regulation of rat mesangial cells. 1074 97

WAVE proteins are members of the Wiskott-Aldrich syndrome protein (WASP) family of scaffolding proteins that coordinate actin reorganization by coupling Rho-related small molecular weight GTPases to the mobilization of the Arp2/3 complex. We identified WAVE-1 in a screen for rat brain A kinase-anchoring proteins (AKAPs), which bind to the SH3 domain of the Abelson tyrosine kinase (Abl). Recombinant WAVE-1 interacts with cAMP-dependent protein kinase (PKA) and Abl kinases when expressed in HEK-293 cells, and both enzymes co-purify with endogenous WAVE from brain extracts. Mapping studies have defined binding sites for each kinase. Competition experiments suggest that the PKA-WAVE-1 interaction may be regulated by actin as the kinase binds to a site overlapping a verprolin homology region, which has been shown to interact with actin. Immunocytochemical analyses in Swiss 3T3 fibroblasts suggest that the WAVE-1 kinase scaffold is assembled dynamically as WAVE, PKA and Abl translocate to sites of actin reorganization in response to platelet-derived growth factor treatment. Thus, we propose a previously unrecognized function for WAVE-1 as an actin-associated scaffolding protein that recruits PKA and Abl.
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PMID:Scar/WAVE-1, a Wiskott-Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold. 1097 Aug 52

C1q may participate in the loss of connective tissue occurring in chronic inflammatory lesions. The hypothesis of a detrimental role of C1q on cell proliferation was tested on primary cultures of human fibroblasts (HFs). C1q suppressed the DNA synthesis of HF in response to platelet-derived growth factor (PDGF) with an IC(50) of 20 microg/ml, and blocked 78% of the cycling cells in G(1) phase. The C1q block did not involve production of inhibitory prostaglandin by the cells. Given that C1q elicits signals of the adenylyl cyclase pathway in HF, we examined cAMP-dependent mechanisms to understand how C1q inhibited the PDGF response. Whereas the C1q block was enhanced by agonist dibutyryl-adenosine 3', 5'-cyclic mono-phosphate (db-cAMP), antagonist adenosine 3', 5'-cyclic monophosphorotioate triethylammonium salt (Rp-cAMP) minimized it. C1q increased the level of cAMP-dependent protein kinase I (PKA-I) 4.5-fold, without altering the activation of the extracellular-regulated protein kinase (ERK) pathway. These results demonstrate that the interactions of C1q with HF cause growth arrest at the G(1) phase through mechanisms associated with a PKA-I dependent pathway.
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PMID:C1q arrests the cell cycle progression of fibroblasts in G(1) phase: role of the cAMP/PKA-I pathway. 1125 56

A rate-limiting step of tumor cell metastasis is matrix degradation by active matrix metalloproteinases (MMPs). It is known that reactive oxygen species are involved in tumor metastasis. Sustained production of H(2)O(2) by phenazine methosulfate (PMS) induced activation of pro-MMP-2 through the induction of membrane type 1-MMP (MT1-MMP) expression in HT1080 cells. MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 and -2 levels were changed negligibly by PMS. A one time treatment with H(2)O(2) did not induce activation of MMPs. It was also demonstrated that superoxide anions and hydroxyl radicals were not related to PMS action. PMS-induced pro-MMP-2 activation was regulated by the receptor tyrosine kinases, especially the receptors of platelet-derived growth factor and vascular endothelial growth factor, and downstream on the phosphatidylinositol 3-kinase/NF-kappa B pathway but not Ras, cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinases. PMS did not induce pro-MMP-2 activation in T98G and NIH3T3 cells. This may be related to a low level of MT1-MMP, indicating a threshold level of MT1-MMP is important for pro-MMP-2 activation. Furthermore, PMS increased cell motility and invasion but decreased cell-cell interaction. Cell-matrix interaction was not affected by PMS.
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PMID:Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. 1205 32

The controlled accumulation of fibroblasts to sites of inflammation is crucial to effective tissue repair after injury. Either inadequate or excessive accumulation of fibroblasts could result in abnormal tissue function. Prostacyclin (PGI(2)) is a potent mediator in the coagulation and inflammatory processes. The aim of this study was to investigate the effect of PGI(2) on chemotaxis of human fetal lung fibroblasts (HFL-1). Using the blind well chamber technique, we found that the PGI(2) analog carbaprostacyclin (10(-6) M) inhibited HFL-1 chemotaxis to human plasma fibronectin (20 microg/ml) 58.0 +/- 13.2% (P < 0.05) and to platelet-derived growth factor (PDGF)-BB (10 ng/ml) 48.7 +/- 4.6% (P < 0.05). Checkerboard analysis demonstrated that carbaprostacyclin inhibits both directed and undirected migration. The inhibitory effect of the carbaprostacyclin was concentration dependent and blocked by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, suggesting that a cAMP-PKA pathway may be involved in the process. Two other PGI(2) analogs, ciprostene and dehydro-15-cyclohexyl carbaprostacyclin (both 10(-6) M), significantly inhibited fibroblast migration to fibronectin. In summary, PGI(2) appears to inhibit fibroblast chemotaxis to fibronectin and PDGF-BB. Such an effect may contribute to the regulation of fibroblasts in wound healing and could contribute to the pathogenesis of diseases characterized by abnormal tissue repair remodeling.
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PMID:Prostacyclin analogs inhibit fibroblast migration. 1211 5

Spatial regulation of the cAMP-dependent protein kinase (PKA) is required for chemotaxis in fibroblasts; however, the mechanism(s) by which PKA regulates the cell migration machinery remain largely unknown. Here we report that one function of PKA during platelet-derived growth factor (PDGF)-induced chemotaxis was to promote membrane ruffling by regulating phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) dynamics. Inhibition of PKA activity dramatically altered membrane dynamics and attenuated formation of peripheral membrane ruffles in response to PDGF. PKA inhibition also significantly decreased the number and size of PIP(3)-rich membrane ruffles in response to uniform stimulation and to gradients of PDGF. This ruffling defect was quantified using a newly developed method, based on computer vision edge-detection algorithms. PKA inhibition caused a marked attenuation in the bulk accumulation of PIP(3) following PDGF stimulation, without effects on PI3-kinase (PI3K) activity. The deficits in PIP(3) dynamics correlated with a significant inhibition of growth factor-induced membrane recruitment of endogenous Akt and Rac activation in PKA-inhibited cells. Simultaneous inhibition of PKA and Rac had an additive inhibitory effect on growth factor-induced ruffling dynamics. Conversely, the expression of a constitutively active Rac allele was able to rescue the defect in membrane ruffling and restore the localization of a fluorescent PIP(3) marker to membrane ruffles in PKA-inhibited cells, even in the absence of PI3K activity. These data demonstrate that, like Rac, PKA contributes to PIP(3) and membrane dynamics independently of direct regulation of PI3K activity and suggest that modulation of PIP(3)/3-phosphatidylinositol (3-PI) lipids represents a major target for PKA in the regulation of PDGF-induced chemotactic events.
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PMID:Protein kinase A regulates 3-phosphatidylinositide dynamics during platelet-derived growth factor-induced membrane ruffling and chemotaxis. 1893 99


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