Phosphorylation of the precursor sequence of rat B-type natriuretic peptide by p34cdc2 and MAP kinase

1994 ◽  
Vol 72 (5-6) ◽  
pp. 227-232 ◽  
Author(s):  
Vasek A. Mezl ◽  
Mark H. Watson ◽  
T. Geoffrey Flynn ◽  
Alan S. Mak
Keyword(s):  
Protein Kinase ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Leader Sequence ◽  
Mitogen Activated Protein Kinase ◽  
Phosphorylation Sites ◽  
Sea Star ◽  
Mitogen Activated Protein ◽  
Atrial Natriuretic

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), two distinct members of the natriuretic peptide family, share many features in common. However, differences in expression indicate that the processing mechanisms must be different. The leader sequence of rat BNP contains three potential phosphorylation sites for proline-directed kinases that are not present in the leader sequence of ANP. This study has examined how these sites are used by two somewhat different proline-directed kinases. A peptide containing these sites was phosphorylated in vitro by HeLa p34cdc2 kinase and by sea star p44mpk kinase at rates that were comparable to the rates with peptide substrates that are used to assay these enzymes. Sequence analysis of the phosphopeptide shows that both kinases phosphorylate only the two potential phosphorylation sites surrounding the cleavage site of the BNP precursor. The enzymatic potential for such a phosphorylation of BNP in cardiac tissue is demonstrated by immunoblots and kinase assays, showing that in fetal and in adult rat heart both the atria and the ventricles contain a mitogen-activated protein kinase homologue that can phosphorylate this preproBNP sequence.Key words: atrial natriuretic peptide, cdc2 kinase, mitogen-activated protein kinase, phosphorylation.

scholarly journals Atrial Natriuretic Peptide Inhibits Mitogen-activated Protein Kinase through the Clearance Receptor

1996 ◽  
Vol 271 (24) ◽  
pp. 14156-14162 ◽  
Author(s):  
Bruce A. Prins ◽  
Michael J. Weber ◽  
Ren-Ming Hu ◽  
Ali Pedram ◽  
Mark Daniels ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Clearance Receptor ◽  
Atrial Natriuretic

scholarly journals Effect of Luminal Atrial Natriuretic Peptide on Chloride Reabsorption in Mouse Cortical Thick Ascending Limb

2000 ◽  
Vol 11 (10) ◽  
pp. 1791-1797
Author(s):  
CLAIRE BAILLY
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Specific Inhibitor ◽  
Guanosine Monophosphate ◽  
Thick Ascending Limb ◽  
Kinase C ◽  
Atrial Natriuretic

Abstract. Insofar as neutral endopeptidase inhibition has afforded evidence for a tubular luminal action of atrial natriuretic peptide (ANP), the present study was undertaken to investigate a possible effect of the peptide on chloride reabsorption (JCl) in thick ascending limb (TAL). Luminal addition of ANP to in vitro microperfused cortical TAL (CTAL) significantly decreased JCl with a threshold and a maximum concentration of 10-12 M and 10-9 M, respectively. A similar effect of 10-9 M ANP was observed in medullary TAL (MTAL). The effect of luminal ANP was significantly reduced by HS-142-1, a specific inhibitor of guanylyl cyclase receptor, and by H-8, a protein kinase G inhibitor, but was not affected by the protein kinase C inhibitor bisindolylmaleimide I. Unexpectedly, the effect of ANP was not additive with that of endothelin (ET), a peptide that was previously shown to decrease JCl in TAL through a calcium-independent, protein kinase C—mediated pathway. Indeed, ET-1 (10-8 M in the lumen) significantly decreased JCl and prevented a further effect of ANP on the same tubule. Similarly, the decrease of JCl induced by simultaneous addition of ET and ANP was not higher than that obtained with each agent alone. Conversely, the inhibitory effect of ANP was enhanced in the presence of cyclic guanosine monophosphate (cGMP; 10-6 M in the lumen). ET-1 significantly attenuated the ANP-stimulated generation of cGMP in microdissected CTAL and failed to prevent a further decrease of JCl promoted by a permeant cGMP analogue. It is concluded that luminal ANP decreased Cl reabsorption in mouse CTAL and MTAL. This effect was abrogated by ET-1 as a result of the inhibition of ANP-stimulated cGMP generation.

scholarly journals Cardiac hormones for the treatment of cancer

2013 ◽  
Vol 20 (3) ◽  
pp. R113-R125 ◽  
Author(s):  
David L Vesely
Keyword(s):  
Protein Kinase ◽  
Cancer Cells ◽  
Natriuretic Peptide ◽  
Mitogen Activated Protein Kinase ◽  
Breast Cancers ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Cardiac Hormones ◽  
Long Acting

Four cardiac hormones, namely atrial natriuretic peptide, vessel dilator, kaliuretic peptide, and long-acting natriuretic peptide, reduce up to 97% of all cancer cellsin vitro. These four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas, two-thirds of human breast cancers, and up to 80% of human pancreatic adenocarcinomas growing in athymic mice. Their anticancer mechanisms of action, after binding to specific receptors on cancer cells, include targeting the rat sarcoma-bound GTP (RAS) (95% inhibition)–mitogen-activated protein kinase kinase 1/2 (MEK 1/2) (98% inhibition)–extracellular signal-related kinase 1/2 (ERK 1/2) (96% inhibition) cascade in cancer cells. They also inhibit MAPK9, i.e. c-Jun N-terminal kinase 2. They are dual inhibitors of vascular endothelial growth factor (VEGF) and its VEGFR2 receptor (up to 89%). One of the downstream targets of VEGF is β-catenin, which they reduce up to 88%. The WNT pathway is inhibited up to 68% and secreted frizzled-related protein 3 decreased up to 84% by the four cardiac hormones. AKT, a serine/threonine protein kinase, is reduced up to 64% by the cardiac hormones. STAT3, a final ‘switch’ that activates gene expression that leads to malignancy, is decreased by up to 88% by the cardiac hormones. STAT3 is specifically decreased as they do not affect STAT1. There is a cross-talk between the RAS–MEK 1/2–ERK 1/2 kinase cascade, VEGF, β-catenin, WNT, JNK, and STAT pathways and each of these pathways is inhibited by the cardiac hormones.

scholarly journals Cross-talk between IRAK-4 and the NADPH oxidase1

2007 ◽  
Vol 403 (3) ◽  
pp. 451-461 ◽  
Author(s):  
Sandrine Pacquelet ◽  
Jennifer L. Johnson ◽  
Beverly A. Ellis ◽  
Agnieszka A. Brzezinska ◽  
William S. Lane ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Free System ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Tlr4 Activation

Exposure of neutrophils to LPS (lipopolysaccharide) triggers their oxidative response. However, the relationship between the signalling downstream of TLR4 (Toll-like receptor 4) after LPS stimulation and the activation of the oxidase remains elusive. Phosphorylation of the cytosolic factor p47phox is essential for activation of the NADPH oxidase. In the present study, we examined the hypothesis that IRAK-4 (interleukin-1 receptor-associated kinase-4), the main regulatory kinase downstream of TLR4 activation, regulates the NADPH oxidase through phosphorylation of p47phox. We show that p47phox is a substrate for IRAK-4. Unlike PKC (protein kinase C), IRAK-4 phosphorylates p47phox not only at serine residues, but also at threonine residues. Target residues were identified by tandem MS, revealing a novel threonine-rich regulatory domain. We also show that p47phox is phosphorylated in granulocytes in response to LPS stimulation. LPS-dependent phosphorylation of p47phox was enhanced by the inhibition of p38 MAPK (mitogen-activated protein kinase), confirming that the kinase operates upstream of p38 MAPK. IRAK-4-phosphorylated p47phox activated the NADPH oxidase in a cell-free system, and IRAK-4 overexpression increased NADPH oxidase activity in response to LPS. We have shown that endogenous IRAK-4 interacts with p47phox and they co-localize at the plasma membrane after LPS stimulation, using immunoprecipitation assays and immunofluorescence microscopy respectively. IRAK-4 was activated in neutrophils in response to LPS stimulation. We found that Thr133, Ser288 and Thr356, targets for IRAK-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after LPS stimulation. We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation.

Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes

1993 ◽  
Vol 13 (9) ◽  
pp. 5659-5669 ◽  
Author(s):  
M Tyers ◽  
B Futcher
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
G1 Phase ◽  
Transduction Pathway ◽  
Yeast Saccharomyces Cerevisiae ◽  
Alpha Factor ◽  
Mitogen Activated Protein

In the yeast Saccharomyces cerevisiae, the Cdc28 protein kinase controls commitment to cell division at Start, but no biologically relevant G1-phase substrates have been identified. We have studied the kinase complexes formed between Cdc28 and each of the G1 cyclins Cln1, Cln2, and Cln3. Each complex has a specific array of coprecipitated in vitro substrates. We identify one of these as Far1, a protein required for pheromone-induced arrest at Start. Treatment with alpha-factor induces a preferential association and/or phosphorylation of Far1 by the Cln1, Cln2, and Cln3 kinase complexes. This induced interaction depends upon the Fus3 protein kinase, a mitogen-activated protein kinase homolog that functions near the bottom of the alpha-factor signal transduction pathway. Thus, we trace a path through which a mitogen-activated protein kinase regulates a Cdc2 kinase.

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