Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids.

Takai, Yoshimi; Kishimoto, Akira; Iwasa, Yasushi; Kawahara, Yasuhiro; Mori, T; Nishizuka, Yasutomi

doi:10.1016/s0021-9258(18)50638-4

Cited by 1,074 publications

(53 citation statements)

References 25 publications

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“…The PLA isoforms represent the most abundant family of phospholipases, nonetheless, PLC is the most known type of phospholipase. As mentioned earlier, this enzyme catalyzes the hydrolysis of PIP 2 to form DAG and IP 3 that are second messengers involved in calcium-mediated signaling (i.e., IP 3 ) and activation of PKC (i.e., DAG) [9,10]. PKC has long been known for its role in signal transduction and given the plethora of substrates, a multiplicity of functions has been attributed to this enzyme including receptor desensitization, transcriptional regulation, cell growth, memory and learning modulation.…”

Section: Lipids In Signal Transductionmentioning

confidence: 96%

“…PIP 2 is the precursor of 1,2-diacyglycerol (DAG) and inositol 1,4,5-trisphosphate (IP 3 ). These molecules are formed in the presence of phospholipase C (PLC) and serve as second messengers in cell signaling triggering the release of calcium from deposits in the endoplasmic reticulum (i.e., IP 3 ) and stimulating the activity of protein kinase C (i.e., DAG), respectively [9,10]. Independent work from two research groups led to the identification of a novel protein kinase (i.e., PI3K) able to catalyze the phosphorylation of inositol phospholipids on the 3 position of the inositol molecule (PtdIns(3)P) in fibroblasts stimulated with platelet-derived growth factor (PDGF) [11][12][13] and a novel phosphoinositide containing four phosphate groups (PtdInsP 3 or PIP 3 ) found in activated neutrophils from human donors [14].…”

Section: Lipids In Signal Transductionmentioning

confidence: 99%

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Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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Uncontrolled proliferation is a feature defining cancer and it is linked to the ability of cancer cells to effectively adapt their metabolic needs in response to a harsh tumor environment. Metabolic reprogramming is considered a hallmark of cancer and includes increased glucose uptake and processing, and increased glutamine utilization, but also the deregulation of lipid and cholesterol-associated signal transduction, as highlighted in recent years. In the first part of the review, we will (i) provide an overview of the major types of lipids found in eukaryotic cells and their importance as mediators of intracellular signaling pathways (ii) analyze the main metabolic changes occurring in cancer development and the role of oncogenic signaling in supporting aberrant lipid metabolism and (iii) discuss combination strategies as powerful new approaches to cancer treatment. The second part of the review will address the emerging role of CK2, a conserved serine/threonine protein kinase, in lipid homeostasis with an emphasis regarding its function in lipogenesis and adipogenesis. Evidence will be provided that CK2 regulates these processes at multiple levels. This suggests that its pharmacological inhibition combined with dietary restrictions and/or inhibitors of metabolic targets could represent an effective way to undermine the dependency of cancer cells on lipids to interfere with tumor progression.

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Section: Lipids In Signal Transductionmentioning

confidence: 96%

Section: Lipids In Signal Transductionmentioning

confidence: 99%

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Guerra

Issinger

2020

Pharmaceuticals

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“…It also seems possible th at phosphatidate derived from diacylglycerol may act a Ca2+ ionophore (Tyson et al 1976;Michell et al 1977;Serhan et al 1981). Diacylglycerol (Bell et al 1979) and phos phatidate (Billah et al 1981) are known to supply arachidonate for prostaglandin synthesis, since most phosphatidylinositol molecules in mammalian tissues contain arachidonate at position 2 (Marcus et al 1969; Holub suggested that diacylglycerol derived from phosphatidylinositol plays roles in the transjncmbrsne control of protein phosphorylation through activation of a novel protein kinase, which is tentatively referred to as C-kinase (Takai 1979;Kishimoto et al 1980). The protein kinase absolutely requires Ca2+ and phospholipid, particularly phosphatidylserine for enzymatic activity, but at physiologically low concentrations of Ga2-* -the enzyme seems to be dependent solely upon diacylglycerol for its activation.…”

Section: P Roposed Functions Of Phosphatidylinositol Turnovermentioning

confidence: 99%

“…[OADG] 0.25 0.5 [A23187] unit ml 1 mg ml 1 tion of 40 k protein, nor does it cause release of serotonin at the concentration employed in the present experiment. However, the Ca2+ ionophore at higher than micromolar concentrations itself causes the phosphorylation of 40 k protein as well as serotonin release, probably because of an enhancement of non-specific degradation of phospholipid, and also because of activation of C-kinase by a large increase in Ca2+ concentrations (Takai al. 1979;Kishimoto et al 1980;Kaibuchi et al 1981).…”

Section: O Aoi Ai Omentioning

confidence: 99%

Calcium, phospholipid turnover and transmembrane signalling

Nishizuka

1983

Phil. Trans. R. Soc. Lond. B

152

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Turnover of phosphatidylinositol, which is provoked by various neurotransmitters, peptide hormones and many other biologically active substances, appears to serve as a signal for the transmembrane control of protein phosphorylation through activation of a novel protein kinase (C-kinase). The activation of this enzyme absolutely requires Ca2+ and phosphatidylserine. Diacylglycerol derived from the receptor-linked breakdown of phosphatidylinositol dramatically increases the affinity of C-kinase for Ca2+, and thereby renders this enzyme fully active without a net increase in the concentration of Ca2+. Under appropriate conditions synthetic diacylglycerol directly added to intact cell systems activates C-kinase fully without interaction with surface receptors. By using such synthetic diacylglycerol and the Ca2+ ionophore A23187, it is shown that either receptor-linked protein phosphorylation or Ca2+ mobilization alone is merely a prerequisite but not a sufficient requirement, and both are synergistically effective for causing a full physiological cellular response. In some tissues cyclic nucleotides, both cyclic AMP and cyclic GMP, may inhibit the receptor-linked breakdown of phosphatidylinositol, and appear to provide negative control that prevents over-response.

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“…Apoptotic cell death decreases when Neuro 2A cells are enriched with docosahexaenoic acid (DHA, 22:6v3), and it is thought that the protective effect of DHA is mediated by the accumulation of PS (Kim et al, 2000). In addition to acting at the cellular level, PS lipids have been shown to coactivate (with diacylglycerol) protein kinase C (Takai et al, 1979), an enzyme implicated in signal transduction. Apparently, the chemistry of the PS is important in this molecular triggering event (Johnson et al, 1998), even though alternative proposed mechanisms involve membrane physical properties (Slater et al, 1994;Glaser, 1995, 1996;Epand et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Structure and Fluctuations of Charged Phosphatidylserine Bilayers in the Absence of Salt

Petrache

Tristram-Nagle

Gawrisch

et al. 2004

Biophysical Journal

262

228

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Using x-ray diffraction and NMR spectroscopy, we present structural and material properties of phosphatidylserine (PS) bilayers that may account for the well documented implications of PS headgroups in cell activity. At 30 degrees C, the 18-carbon monounsaturated DOPS in the fluid state has a cross-sectional area of 65.3 A(2) which is remarkably smaller than the area 72.5 A(2) of the DOPC analog, despite the extra electrostatic repulsion expected for charged PS headgroups. Similarly, at 20 degrees C, the 14-carbon disaturated DMPS in the gel phase has an area of 40.8 A(2) vs. 48.1 A(2) for DMPC. This condensation of area suggests an extra attractive interaction, perhaps hydrogen bonding, between PS headgroups. Unlike zwitterionic lipids, stacks of PS bilayers swell indefinitely as water is added. Data obtained for osmotic pressure versus interbilayer water spacing for fluid phase DOPS are well fit by electrostatic interactions calculated for the Gouy-Chapman regime. It is shown that the electrostatic interactions completely dominate the fluctuational pressure. Nevertheless, the x-ray data definitively exhibit the effects of fluctuations in fluid phase DOPS. From our measurements of fluctuations, we obtain the product of the bilayer bending modulus K(C) and the smectic compression modulus B. At the same interbilayer separation, the interbilayer fluctuations are smaller in DOPS than for DOPC, showing that B and/or K(C) are larger. Complementing the x-ray data, (31)P-chemical shift anisotropy measured by NMR suggest that the DOPS headgroups are less sensitive to osmotic pressure than DOPC headgroups, which is consistent with a larger K(C) in DOPS. Quadrupolar splittings for D(2)O decay less rapidly with increasing water content for DOPS than for DOPC, indicating greater perturbation of interlamellar water and suggesting a greater interlamellar hydration force in DOPS. Our comparisons between bilayers of PS and PC lipids with the same chains and the same temperature enable us to focus on the effects of these headgroups on bilayer properties.

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Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids.

Cited by 1,074 publications

References 25 publications

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Calcium, phospholipid turnover and transmembrane signalling

Structure and Fluctuations of Charged Phosphatidylserine Bilayers in the Absence of Salt

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