Oncogenes, ions, and phospholipids

1985 ◽  
Vol 248 (1) ◽  
pp. C3-C11 ◽  
Author(s):  
I. G. Macara
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinases ◽  
Phorbol Esters ◽  
Second Messengers ◽  
Future Research ◽  
Lipid Biochemistry ◽  
Cytosolic Ph ◽  
Pi Turnover ◽  
Transport Studies ◽  
Kinase C

Recent discoveries in tumor virology, lipid biochemistry, and ion transport studies promise to revolutionize our understanding of cell proliferation, differentiation, and tumorigenesis. A model is proposed, based on similar schemes presented recently by others, that incorporates these discoveries and provides a focus for future research on the functions of oncogene proteins. The model suggests that the early (competence) events in the initiation of cell proliferation are triggered by activation of phosphatidylinositol (PI) turnover, which releases two second messengers, 1,2-diacylglycerol (1,2-DG) and inositol-1,4,5-trisphosphate (IP3). PI turnover is proposed to be regulated by the oncogene protein kinases (src, ros, abl, fps) either directly (acting as PI kinases) or indirectly (as tyrosine kinases). The IP3 triggers Ca2+ release from internal stores, and the elevation of cytosolic Ca2+ acts synergistically with 1,2-DG to activate the Ca2+- and phospholipid-dependent kinase C. Kinase C copurifies with the receptor for the tumor-promoting phorbol esters. It is suggested that kinase C then activates the Na+-H+ exchange system, resulting in an elevation of cytosolic pH and Na+, and that these ionic signals (including the change in Ca2+), either in concert or individually, induce further events, including expression of the protooncogene c-myc, which together commit the cell to initiate replication. Evidences in support of this model are reviewed, together with complications indicating its present inadequacies, particularly recent data suggesting that 1,2-DG may activate tyrosine kinases independent of kinase C.

Involvement of PDGF in pressure-induced mesangial cell proliferation through PKC and tyrosine kinase pathways

1999 ◽  
Vol 277 (1) ◽  
pp. F105-F112 ◽  
Author(s):  
Hiroaki Kato ◽  
Akihiko Osajima ◽  
Yasuhito Uezono ◽  
Masahiro Okazaki ◽  
Yuki Tsuda ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Dna Synthesis ◽  
Tyrosine Kinases ◽  
Mechanical Stretch ◽  
Transmural Pressure ◽  
Kinase C

In glomerular hypertension, mesangial cells (MC) are subjected to at least two physical forces: mechanical stretch and high transmural pressure. Increased transmural pressure, as well as mechanical stretch, promotes MC proliferation, which may enhance glomerulosclerosis. The exact mechanism of this effect is not fully understood. We examined the effects of transmural pressure alone on cell proliferation and DNA synthesis and investigated the role of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), candidates for mediation of glomerular diseases, in the pressure-induced events. Pressure was applied to cultured MC placed in a sealed chamber using compressed helium gas. Application of pressure resulted in a time-dependent (∼2 h) and pressure level-dependent (∼80 mmHg) increase in cell number (1.4-fold) and [3H]thymidine incorporation (2.7-fold). Pressure-induced DNA synthesis was significantly suppressed by inhibitors of phospholipase C (2-nitro-4-carboxyphenyl- N, N-diphenylcarbamate), protein kinase C [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine], or tyrosine kinases (genistein). Pressure caused a rapid but transient formation of inositol 1,4,5-trisphosphate, which was blocked by the phospholipase C inhibitor. Pressure also promoted a rapid increase in tyrosine kinase activity. Pressure increased mRNA levels of PDGF-B, with a peak at 6 h, but not those of PDGF-A or bFGF. Pressure-induced DNA synthesis was partially inhibited by a neutralizing anti-PDGF antibody but not by an antibody against bFGF or nonimmune IgG. Our results indicated that pressure by itself increases DNA synthesis and proliferation of cultured rat MC possibly through activation of protein kinase C and tyrosine kinases, and PDGF-B could be partially involved in these pathways.

scholarly journals Relationship between phosphorylation and translocation to the plasma membrane of p47phox and p67phox and activation of the NADPH oxidase in normal and Ca2+-depleted human neutrophils

1993 ◽  
Vol 290 (1) ◽  
pp. 173-178 ◽  
Author(s):  
S Dusi ◽  
V Della Bianca ◽  
M Grzeskowiak ◽  
F Rossi
Keyword(s):  
Plasma Membrane ◽  
Nadph Oxidase ◽  
Phorbol Esters ◽  
Second Messengers ◽  
Human Neutrophils ◽  
Phosphorylated Proteins ◽  
Kinase C ◽  
Activated State ◽  
Phagocyte Oxidase ◽  
Hydrolysis Of

Stimulation of neutrophils with different agonists activates a latent multicomponent NADPH oxidase that reduces molecular oxygen to superoxide anion. Evidence has accumulated that phosphorylation of p47phox (the 47 kDa cytosolic phagocyte oxidase factor) and translocation of the two cytosolic components p47phox and p67phox are essential steps in the activation of NADPH oxidase in response to phorbol esters. We analysed the relationships between activation of the NADPH oxidase and phosphorylation and translocation of p47phox and p67phox in normal and Ca(2+)-depleted neutrophils stimulated by the receptor-mediated agonists formyl-methionyl-leucyl-phenylalanine and concanavalin A. The results produced the following conclusions: (1) Translocation of p47phox and p67phox is an essential mechanism for activation of the NADPH oxidase. (2) A continuous translocation of p47phox and p67phox is necessary to maintain the NADPH oxidase in an activated state. (3) Only a fraction of p47phox and p67phox translocated to the plasma membrane is functional for the activation of the oxidase. (4) Translocation is independent of protein kinase C, and is linked to transmembrane signalling involving Ca2+ transients and production of lipidic second messengers. However, under some conditions, such as in Ca(2+)-depleted neutrophils, translocation can also occur independently of signalling pathways involving production of second messengers from hydrolysis of phospholipids and Ca2+ transients. (5) Phosphorylation of p47phox and p67phox can be quantitatively dissociated from translocation, as staurosporine markedly inhibits phosphorylation but not translocation. (6) The activity of NADPH oxidase is not correlated with the amounts of the phosphorylated proteins present in the plasma membrane.

scholarly journals Signalling in Neutrophils: A Retro Look

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Paul H. Naccache
Keyword(s):  
Tyrosine Kinases ◽  
Second Messengers ◽  
Biological Properties ◽  
Present Knowledge ◽  
Polymorphonuclear Neutrophils ◽  
Signalling Pathways ◽  
Surface Receptors ◽  
The Core ◽  
Kinase C ◽  
Functional Responsiveness

This review presents a summary of signalling events related to the activation of human polymorphonuclear neutrophils by a variety of soluble and particulate agonists. It is not intended as a comprehensive review of this vast field or as a presentation of the multiple new aspects of neutrophil functions that are being documented at an ever faster rate. Its aim is rather to focus on multiple aspects of major signalling pathways that, in the view of this reviewer, are currently shadowed by present trends and to provide the core evidence for their implication and the limitations of our present knowledge. More specifically, this review starts with cell surface receptors and some of their functional and biological properties and then moves on to downstream transducers (G proteins) and effectors (the phosphoinositide, tyrosine kinases, and cyclic nucleotide pathways). Classical second messengers (calcium, protein kinase C, polyphosphoinositides, and cyclic nucleotides) are emphasized. It is hoped that this presentation will not only remind present-day investigators of the central role these pathways play in the regulation of the functional responsiveness of neutrophils, but that it will also highlight some of the areas deserving additional investigation.

Phosphatidic acid modulates Cl- secretion in T84 cells: varying effects depending on mode of stimulation

1993 ◽  
Vol 264 (5) ◽  
pp. C1210-C1218 ◽  
Author(s):  
M. Vajanaphanich ◽  
U. Kachintorn ◽  
K. E. Barrett ◽  
J. A. Cohn ◽  
K. Dharmsathaphorn ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phosphatidic Acid ◽  
Phorbol Esters ◽  
Second Messengers ◽  
T84 Cells ◽  
Cl Secretion ◽  
Cyclic Monophosphate ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Cl- secretion in T84 cells evoked by a stimulus that activates protein kinase C, carbachol, was associated with elevated levels of 32P-labeled phosphatidic acid (PA). PA's role in the regulation of Cl- secretion was explored by examining the effect of exogenous PA (10(-4) M) on Cl- secretion and intracellular Ca2+ levels ([Ca2+]i) in monolayers. PA potentiated the effect of carbachol on [Ca2+]i and Cl- secretion, although it did not stimulate Cl- secretion by itself. PA had divergent effects on cyclic nucleotide-dependent Cl- secretion. It delayed Cl- secretion induced by vasoactive intestinal polypeptide [VIP, adenosine 3',5'-cyclic monophosphate (cAMP) dependent] but potentiated that induced by the heat-stable enterotoxin of Escherichia coli (STa; guanosine 3',5'-cyclic monophosphate dependent). PA did not alter AMP or GMP levels, suggesting that PA acts at a site distal to the generation of these second messengers. PA caused a slight increase in phosphorylation of protein kinase C substrates but not of cAMP-dependent protein kinase substrates. However, PA is probably not acting through a classical protein kinase C pathway, because we have previously shown that phorbol esters inhibit carbachol's actions, and the protein kinase C inhibitor staurosporine failed to block the effect of PA on VIP- or STa-stimulated Cl- secretion. Thus PA differentially regulates stimulated Cl- secretion in T84 cells, depending on the nature of the agonist.

THROMBIN, PAF AND VASOPRESSIN-INDUCED RISE OF PLATELET INTRACELLULAR CALCIUM, AGGREGATION AND ATP SECRETION ARE REDUCED BY ANTIOXIDANTS

1987 ◽  
Author(s):  
M G Doni ◽  
D Deana ◽  
A Alexandre
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
Shape Change ◽  
Second Messengers ◽  
Nordihydroguaiaretic Acid ◽  
Human Platelets ◽  
Kinase C ◽  
Atp Secretion ◽  
The One

Physiological agonists induce a rapid increase of cytosolic free Ca2+ concentration ([Ca2+]i) in platelets, as well as shape change, aggregation and1 secretion. They activate a phosphodiesterase which specifically splits polyphosphoinositides, generating the second messengers diacylglycerol, a protein kinase C ativator, and inositol 1,4,5 triphosphate, which releases Ca2+ from the intracellular stores - [Ca2+]i rise and protein kinase C activation are responsible for aggregation and exocytosis.We have now studied the effects of the synthetic antioxidants: butyl-hydroxytoluene (BHT), butyl- hydroxyanisole (BHA), nordihydroguaiaretic acid (NDGA) and the one electron donor 1-1' dimethylferrocene plus ascorbate (FC) on the increase of [Ca2+]i, aggregation and ATP secretion. Human platelets were loaded1 with 20μM quin-2-acetoxymethylester and incubated with aspirin (100μM). Changes in the [Ca2+]. were measured with a spectrofluorimeter. Platelet aggregation and ATP secretion (luciferin/luciferase system) were evaluated in parallel. In the presence of 1mM external Ca2+,0.15 u/ml thrombin induced a [Ca2+]. increase to about 1μM, that was inhibited by 50% and abolished by 25μM and 100μM BHT respectively; [Ca2+]. increase induced by 75 nM PAF, 1μM vasopressin, 10 μM ADP was also inhibited by BHA, NDGA and FC in a range of 30-150 μM. Shape change, aggregation and ATP secretion were also inhibited. In the absence of external Ca2+ (1mM ECTA), 80μM BHT inhibits the [Ca2+]i increase originating only from the intracellular stores. Tumor-promoting phorbol esters induce aggregation and secretion without raising [Ca2+]i; 80 μM BHT induced 80-90% inhibition of aggregation and ATP secretion by 0.12nM TPA. Our results suggest that some free radical dependent reactions are involved both in the processes of platelet activation leading to the increase of [Ca2+]i and in those leading to aggregation and exocytosis.

Identification of a 50-kDa Ca-, cAMP-, and cGMP-dependent epithelial phosphoprotein as a cAMP regulatory protein

1990 ◽  
Vol 258 (5) ◽  
pp. C889-C901 ◽  
Author(s):  
C. Toskulkao ◽  
M. C. Rao
Keyword(s):  
Ion Transport ◽  
Phorbol Esters ◽  
Second Messengers ◽  
Regulatory Protein ◽  
Specific Protein ◽  
Cyclic Monophosphate ◽  
Transport Studies ◽  
Biphasic Effect ◽  
Isoquinoline Derivatives ◽  
Camp And Cgmp

Multiple second messengers, presumably acting via protein phosphorylation mechanisms, regulate flounder intestinal ion transport. We recently reported [C. Toskulkao, N. T. Nash, K. Leach, and M. C. Rao. Am. J. Physiol. 258 (Cell Physiol. 27): C879-C888, 1990] that this tissue possesses adenosine 3',5'-cyclic monophosphate (cAMP)- and guanosine 3',5'-cyclic monophosphate (cGMP)-specific protein kinases, types II and III Ca-calmodulin kinases, and very low levels of protein kinase C. These results correlate with ion transport studies in which cGMP and Ca were shown to inhibit salt absorption, cAMP to increase anion permeability, and phorbol esters to have no effect. In the present study we characterized in detail a 50-kDa protein the phosphorylation of which is regulated by more than one second messenger. The 50-kDa (pI 5.2) phosphoprotein is present in both the cytosol (50 kDa-C) and particulate (50 kDa-P) fractions and appears to be regulated by Ca, cAMP, and cGMP. Although the pI and Mr of the regulated proteins are identical, there are differences in the regulation of 50 kDa-P and 50 kDa-C. The phosphorylation of 50 kDa-P is high in the basal state, and Ca and cGMP enhance this. cAMP has a biphasic effect, increasing it at low and decreasing it at high protein concentrations. The isoquinoline derivatives H-8 [50% effective dose (ED50) approximately 2.3 microM] and H-7 (ED50 approximately 45 microM) inhibit basal 50 kDa-P phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Receptor Tyrosine Kinases: Role in Cancer Progression

2006 ◽  
Vol 13 (5) ◽  
pp. 191-193
Author(s):  
V. Sangwan ◽  
M. Park
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Normal Tissue ◽  
Receptor Tyrosine Kinases ◽  
Tight Control ◽  
Tissue Patterning

Tight control of cell proliferation and morphogenesis in conjunction with programmed cell death (apoptosis) is required to ensure normal tissue patterning. [...]

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