A Novel PAR-1-Type Thrombin Receptor Signaling Pathway: Cyclic AMP-Independent Activation of PKA in SNB-19 Glioblastoma Cells

Zieger, Michael; Tausch, Svetlana; Henklein, Peter; Nowak, G; Kaufmann, Roland

doi:10.1006/bbrc.2001.4683

Cited by 20 publications

(15 citation statements)

References 30 publications

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“…25 PAR-1 has been reported to couple to various heterotrimeric G proteins and conveys its signal through several kinases, including Src family tyrosine kinases, JNK, Rho kinases, mitogen-activated protein K, PKA, and PKC. 17,19 Protein kinases have been found to differentially regulate ion channel gating and trafficking. Upon stimulation, PAR-1 enhances PLC-b-dependent hydrolysis of PIP 2 , which results in DAG and inositol trisphosphate production.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmin-Induced Inhibition of TRPV5 Depends on PKC Phosphorylation of Serine-144 Residue PAR-1 is a member of the G protein-coupled receptor family, which normally exerts its effect through the PKA 17 or PLC/PKC pathways. 18 We investigated whether these protein kinases are involved in plasmin-activated PAR-1 signaling.…”

Section: Plasmin Does Not Affect Trpv5 Membrane Abundancementioning

confidence: 99%

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Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Tudpor

Laínez

Kwakernaak

et al. 2012

Journal of the American Society of Nephrology

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Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca 2+ reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca 2+ uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patchclamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca 2+ uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5. 23: 182423: -183423: , 201223: . doi: 10.1681 In the kidney, the fine regulation of Ca 2+ balance occurs through the activity of the epithelial Ca 2+ channel TRPV5. 1 TRPV5 is mostly expressed in the distal convoluted tubule (DCT) and connecting tubule of the nephron, where it constitutes the apical entry mechanism for transcellular Ca 2+ reabsorption. TRPV5 is a constitutively active ion channel that bears unique electrophysiologic characteristics, including calmodulin (CaM) and Ca 2+ -dependent inactivation and high selectivity for Ca 2+ . 2,3 The activity of TRPV5 is tightly controlled at multiple levels by an array of different factors, including parathyroid hormone and the serine protease tissue kallikrein. Both parathyroid hormone and tissue kallikrein initiate the phosphorylation of TRPV5 through the cAMP/protein kinase A (PKA) and phospholipase C (PLC)/ diacylglycerol (DAG)/protein kinase C (PKC) signaling cascades, respectively. 4,5 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Section: Plasmin Does Not Affect Trpv5 Membrane Abundancementioning

confidence: 99%

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Tudpor

Laínez

Kwakernaak

et al. 2012

Journal of the American Society of Nephrology

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“…This family has a strong preference for the phosphorylation of Ser and Thr residues located in a consensus sequence containing the basic amino acid Lys or Arg (19). They are activated by an elevated cellular concentration of the second messenger cAMP (20), although their activation independent of cAMP has also been reported (21,22). Many studies have shown that the cAMP-PKA module is involved in the regulation of NF-B signaling through the phosphorylation of p65 or p105 in a positive or negative manner, depending on cell type (16,(23)(24)(25)(26).…”

Section: Tgf-␤-activated Kinase 1 (Tak1) Is a Key Kinase In Mediatingmentioning

confidence: 99%

Transforming Growth Factor (TGF)-β-activated Kinase 1 (TAK1) Activation Requires Phosphorylation of Serine 412 by Protein Kinase A Catalytic Subunit α (PKACα) and X-linked Protein Kinase (PRKX)

Ouyang

Nie

et al. 2014

Journal of Biological Chemistry

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Background: Understanding of molecular mechanism of TAK1 activation is incomplete. Results: PKAC␣ and PRKX phosphorylate TAK1 at serine 412 to regulate TAK1 activation in the IL-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling pathways. Conclusion: TAK1 activation requires phosphorylation by PKAC␣ and PRKX. Significance: This study advanced our understanding of the molecular mechanism of TAK1 activation.

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“…This signaling pathway uses activation of PKA via anchoring proteins such as AKAP110 42 and NF-B. 43 Despite an established role for PKA in barrier protection, PKA targets involved in endothelial barrier function remain largely unknown. The focal adhesion-and microfilament-associated protein VASP is a known PKA target.…”

Section: Kolosova Et Al Atp-induced Endothelial Cell Barrier Enhancementmentioning

confidence: 99%

Signaling Pathways Involved in Adenosine Triphosphate-Induced Endothelial Cell Barrier Enhancement

Kolosova

Mirzapoiazova

Adyshev

et al. 2005

Circulation Research

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Abstract-Endothelial barrier dysfunction caused by inflammatory agonists is a frequent underlying cause of vascular leak and edema. Novel strategies to preserve barrier integrity could have profound clinical impact. Adenosine triphosphate (ATP) released from endothelial cells by shear stress and injury has been shown to protect the endothelial barrier in some settings. We have demonstrated that ATP and its nonhydrolyzed analogues enhanced barrier properties of cultured endothelial cell monolayers and caused remodeling of cell-cell junctions. Increases in cytosolic Ca 2ϩ and Erk activation caused by ATP were irrelevant to barrier enhancement. Experiments using biochemical inhibitors or siRNA indicated that G proteins (specifically G ␣q and G ␣i2 ), protein kinase A (PKA), and the PKA substrate vasodilator-stimulated phosphoprotein were involved in ATP-induced barrier enhancement. ATP treatment decreased phosphorylation of myosin light chain and specifically activated myosin-associated phosphatase. Depletion of G ␣q with siRNA prevented ATP-induced activation of myosin phosphatase. We conclude that the mechanisms of ATP-induced barrier enhancement are independent of intracellular Ca 2ϩ , but involve activation of myosin phosphatase via a novel G-protein-coupled mechanism and PKA. Key Words: endothelial barrier Ⅲ extracellular adenosine triphosphate Ⅲ G protein Ⅲ myosin phosphatase I nflammatory agonist-induced endothelial cell (EC) barrier dysfunction is associated with cytoskeletal remodeling, disruption of cell-cell contacts, and the formation of paracellular gaps. 1 Less is known about the mechanisms of EC barrier maintenance and protection. Some naturally occurring substances such as sphingosine 1-phosphate, angiotensin 1, and the second messenger cAMP are known to enhance the EC barrier. Recently, much attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. 2 Accumulated experimental data suggest that adenosine triphosphate (ATP) and other purines are promising as physiologically-relevant barrier-protective agents as they are readily present in the surrounding EC microenvironment in vivo, and they decrease transendothelial permeability in vitro. ATP can be released into the bloodstream from platelets 3 and red blood cells. 4 Extracellular ATP concentrations may temporarily exceed 100 mol/L in blood. 5 Furthermore, the endothelium provides a source of ATP locally within vascular beds. ATP is released constitutively across the apical membrane of EC under basal conditions. 6 Enhanced release of ATP was observed from EC in response to various stimuli including hypotonic challenge, 6 calcium agonists, 6 shear stress, 7 thrombin, 7 ATP itself, 8 and lipopolysaccharide. 9 Once released, ATP is degraded rapidly and its metabolites, adenosine diphosphate (ADP) and adenosine, have also been characterized as signaling molecules, able to regulate various cellular functions. 10

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A Novel PAR-1-Type Thrombin Receptor Signaling Pathway: Cyclic AMP-Independent Activation of PKA in SNB-19 Glioblastoma Cells

Cited by 20 publications

References 30 publications

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Transforming Growth Factor (TGF)-β-activated Kinase 1 (TAK1) Activation Requires Phosphorylation of Serine 412 by Protein Kinase A Catalytic Subunit α (PKACα) and X-linked Protein Kinase (PRKX)

Signaling Pathways Involved in Adenosine Triphosphate-Induced Endothelial Cell Barrier Enhancement

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