Effects of protein kinase C activation on human platelet cyclic AMP metabolism

Bushfield, Mark; Hopple, S.; Gibson, Iain; Murdoch, Fiona A.; MacIntyre, D. Euan

doi:10.1016/0014-5793(87)80390-3

Cited by 10 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard we should not only take account of the various components involved in the metabolism of cyclic AMP but also the fact that protein kinase C is found in various isoenzymic forms [S, 61, which may have rather different specificities as regards both substrates and activators [7,81, that cells contain a variety of phosphatases, again with different specificities [9] and that activators of protein kinase C may come from the breakdown of not only phosphatidylinositol 4,5-bisphosphate [PtdIns(4,S)P2] but also phosphatidylcholine [lo]. Fig.…”

Section: 'Cross-talk' Between the Cyclic Amp And Protein Kinase C Patmentioning

confidence: 99%

‘Crosstalk’: a pivotal role for protein kinase C in modulating relationships between signal transduction pathways

Houslay

1991

European Journal of Biochemistry

328

View full text Add to dashboard Cite

Over the past 20 years we have seen a phenomenal increase in our understanding ofthe diversity and the molecular mechanism of action of signal transduction systems. Now we are faced with a cell being provided with a myriad of cell surface receptors, each connected to particular signal transduction systems. The very complexity of such systems, together with the need of the cell to monitor and respond to a variety of external stimuli, poses the question as to what overall controls are placed upon these various transduction mechanisms and how they might relate to each other. At one extreme, we can envisage that pathways might be isolated completely from each other and thus function in an an apparent 'vacuum'. On the other hand, we can envisage 'cross-talk' between the various pathways linking each into an adaptable network array. Such a network, linking distinct signalling systems, would offer the cell a sophisticated ability to sense multiple environmental signals impinging upon it, thus providing a means of adapting or regulating its response to a particular range of effectors. In this way the cell might respond to the relative concentrations of various signals, taking into account the particular point in time when it first experienced a specific signal, together with the absolute length of time it was exposed to it. Such parameters having markedly different effects on cellular behaviour. Thus one might envisage that both the 'quantity' and the 'quality' of information flowing through any particular signal transduction system might be altered by the functioning of other transduction systems which were linked to form such an interactive network. A cell controlled in such a fashion could be regarded as being capable of 'learning', Correspondence to

show abstract

Section: 'Cross-talk' Between the Cyclic Amp And Protein Kinase C Patmentioning

confidence: 99%

‘Crosstalk’: a pivotal role for protein kinase C in modulating relationships between signal transduction pathways

Houslay

1991

European Journal of Biochemistry

328

View full text Add to dashboard Cite

show abstract

“…phorbol esters2, 3) and inhibition (e.g. staurosporine4) that a systematic conception of kinase‐inhibitor synthesis began 5. Currently, rationally designed small‐molecule therapies are able to target the deep ATP‐binding groove with high affinity and some binding specificity due to subtle differences within the groove.…”

Section: Introductionmentioning

confidence: 99%

PTK 787/ZK 222584, a Tyrosine Kinase Inhibitor of all Known VEGF Receptors, Represses Tumor Growth with High Efficacy

Hess‐Stumpp¹,

Haberey²,

Thierauch³

2005

ChemBioChem

View full text Add to dashboard Cite

The angiogenesis inhibitor PTK 787/ZK 222584 (PTK/ZK) blocks all known VEGF receptor (VEGFR) tyrosine kinases, including the lymphangiogenic VEGFR3, in the lower nanomolar range. From a panel of 100 kinases only PDGFR, c-kit, and c-fms are inhibited beyond those in the nanomolar range. PTK/ZK functions as a competitive inhibitor at the ATP-binding site of the receptor kinase as shown here in kinetic experiments. The VEGF signal blockade in microvascular endothelial cells (MVEC) results in a blockade of MVEC proliferation (IC50=30 nM), without affecting the proliferation of normal tissue cells and tumor cells. The efficacy of PTK/ZK depends on its continuous presence within the endothelial target cells. Early removal attenuates its antiproliferative activity in vitro. Growth inhibition of endothelial cells is fully reversible as demonstrated by "washout" experiments. Without inhibiting tumor cell proliferation directly, PTK/ZK results in a significant retardation of tumor growth in a number of experimental tumor models of different tissue origin. Combination of PTK/ZK with an antiandrogen revealed additive effects on tumor-growth inhibition. Treatment efficacy was monitored both by tumor weight and by the determination of serum concentrations of the surrogate marker PSA. PTK/ZK is currently being investigated in patients with different solid tumor types for its therapeutic utility. Preliminary data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile, which we interpret to be a consequence of the high selectivity of the drug for a limited number of kinases. Preliminary response, time to progression, and overall survival data were promising.1 Based on these encouraging results, PTK/ZK is currently in Phase III clinical trials for metastatic colorectal cancer.

show abstract

“…The former site is conserved in the EP2 and EP3 subtypes ofthe PGE receptor, whereas the latter is found in the TXA2 and the PGF receptors. In human platelets, phorbol ester treatment abolishes adenylate cyclase activation mediated by the PGD receptor, but spares the response mediated by the PGI receptor (39). Phorbol ester treatment also attenuates TX agonist-induced GTP hydrolysis in platelet membranes (F.U.…”

Section: F-t------hpg25mentioning

confidence: 99%

Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene.

Hirata

Kakizuka

Aizawa

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

208

151

View full text Add to dashboard Cite

Recently, we isolated cDNAs for the TXA2 receptor (15, 16) and the EP1 (17), the EP2 (18), and the EP3 (19,20) subtypes ofthe PGE receptors by homology screening. These studies revealed that prostanoid receptors constitute a subfamily within the rhodopsin-type, G protein-coupled receptor superfamily (21), and they enabled us to identify highly conserved amino acid sequences in these receptors. To clone the cDNAs for other prostanoid receptors, we have carried out reverse transcription polymerase chain reaction (RT-PCR) studies based on such motifs and have successfully amplified three cDNAs encoding sequences homologous to prostanoid receptors. Of these three, one has been identified as being part of the PGF receptor cDNA (22) and another as being part of the PG1 receptor cDNA (23). The third, unidentified, cDNA showed a high degree ofsequence similarity to the PGI receptor (23) and to the EP2 subtype of the PGE receptor (18). We postulated that the cDNA may code for a member ofthe relaxant prostanoid receptor family. Here, we report the primary structure of this mouse cDNA and its gene.t We also describe the identification ofthe gene product MATERIALS AND METHODS Lgands. PGD2, PGE2, PGF2a, and STA2 (9,11-epithio-11,12-methano-TXA2) were kindly provided by Ono Pharmaceuticals (Osaka). BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin] and BW A868C

show abstract

Effects of protein kinase C activation on human platelet cyclic AMP metabolism

Cited by 10 publications

References 20 publications

‘Crosstalk’: a pivotal role for protein kinase C in modulating relationships between signal transduction pathways

‘Crosstalk’: a pivotal role for protein kinase C in modulating relationships between signal transduction pathways

PTK 787/ZK 222584, a Tyrosine Kinase Inhibitor of all Known VEGF Receptors, Represses Tumor Growth with High Efficacy

Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene.

Contact Info

Product

Resources

About