Of phosphatidyl inositols

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

Inhibition of phosphatidyl inositol and protein kinase C signaling pathways... 

Fig. 5.24 Classification of the phospholipases and the reaction of phospholipase C. a) Cleavage specificity of phospholipases Al, A2, C and D. b) Cleavage of inositol-containing phosphohpids by phospholipase C. In a reaction of particnlar importance for signal transduction, phosphohpase C (PL-C) catalyzes the cleavage of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2) into the messenger substances diacylglycerol and inositol 1,4,5-triphosphate (Ins(l,4,5)P3).

Phosphatidyl inositol (Ptdins) is first phosphorylated by specific kinases at the 4 and 5 positions of the inositol residue, leading to formation of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2). 

Fig. 6.9. A) Metabolism of phosphatidyl inositol lipids. The figure shows different membrane-associated phosphatidyl inositol phosphate compounds and their mutual conversion. PI3-kinase (PI3K) is responsible, in particular, for the formation of PtdIns(3,4,5)P3 from PtdIns(3,4)P2. For the reactions marked with a question mark, involvement of PI(3) kinase is not certain.

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

Ge C, Anand-Srivastava MB. 1998. Involvement of phosphatidyl inositol-3-kinase and mitogen-activted protein kinase in All-mediated enhanced expression of Gi proteins in vascular smooth muscle cells. Biochem Biophys Res Commun 251 570-575. 

A number of other factors activate phospholipase C which causes the hydrolysis of phosphatidyl inositol(4,5)bisphosphate to DAG and IP3. Following release the IP3 is rapidly broken down via IP2 and IP3 to inositol in a Li+ sensitive reaction and this is the reason why lithium can desensitise receptors. The inositol then reacts with activated DAG and is rephosphorylated to regenerate phosphatidyl inositol(4,5)bisphosphate (Berridge and Irvine, 1984 Wakelam, 1989). 

Stephens, L. R., Jackson, T. R., and Hawkins, P. T. (1993) Agonist-stimulated synthesis of phosphatidyl inositol (3,4,5)-trisphosphate a new intracellular signalling system Biochim. Biophys. Acta 1179, 27-75. 

The Hydrolysis of Phosphatidyl Inositol Bisphosphate by Phospholipase C Generates Two Messengers... 

Likewise, phosphatidyl inositol is formed by the transfer of a diacylglycerol phosphate unit from CDP-diacylglycerol to inositol. Subsequent phosphorylations catalyzed by specific kinases lead to the synthesis of phosphatidyl inositol 4,5-bisphosphate, an important molecule in signal transduction. Recall that hormonal and sensory stimuli activate phospholipase C, an enzyme that hydrolyzes this phospholipid to form two intracellular messengers—diacylglycerol and inositol 1,4,5-trisphosphate (Section 15.2). 

Phospholipase C (both p and y) catalyzes the hydrolysis of Phosphatidyl inositol bisphosphate (PIPj) leading to the generation of diacylglycerol (DAG) and inositol trisphosphate (IP,). In platelets, thrombin and thromboxane-A, (TxA,) stimulate PLC-p. PLC-P has three isotypes. It is known that PLC-pi and PLC-P3 are activated by G-protein... 

FIGURE 9.98 Events taking place in the plasma membrane on stimulation of a cell. Phospha tidylinositol (Pi) and more hi ly phosphoiylated versions of this lipid account for 2 to 8% of the lipids of the plasma membrane of eukaryotic cdIs. The inositol 1,4,5 triphosphate (fP3) moiety of phosphatidyl inositol- 4,8-di phosphate may be hydiulyitec from this lipid immediately after the cell is stimulated. For example, the stimulation of platelets by thrombin or the islets of the pancreas by glucose is followed by the release of 1P3 into the cytoplasm. In some cells, arachidonic acid is hydrolyzed from l-acyl-2-arachidonyl-glyceroL which can Support a burst of prostaglandin. synthesis. 

In a study on human promyelocytic leukaemia HL-60 cells, quercetin reduced cellular groAvth dose-dependently, and abolished it at a concentration of 80 pM. This effect was attributed to the concomitant inhibition of membrane, but not cytosolic, PTK activity, determined on poly Glu-Tyr (4 1) as a substrate (IC50 = 20.1 pM), Inversely, quercetin inhibited cytosolic, but not membrane, PKC activity. As a possible result of the inhibition of phosphatidyl-inositol kinases, the production of phosphoinositides in intact HL-60 cells was greatly diminished by quercetin [46]. 

Figure 14,12 Phosphoinositide cascade. The cleavage of phosphatidyl inositol 4,5-bisphosphate (PIP ) into diacyiglycerol (DAG) and inositol 1,4,5-trisphosphate (IP5) results in the release of calcium ions (due to the opening of the IP3 receptor ion channels) and the activation of protein kinase C (due to the binding of protein kinase C to free DAG in the membrane). Calcium ions bind to protein kinase C and help facilitate its activation.

The answer is c. (Murray, pp 238-249. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) A variety of agonists activate the plasma membrane-bound enzyme phospholipase C, which hydrolyzes the phosphodiester bond of phosphatidyl inositol 4,5-bisphosphate and consequently releases diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). Phospholipase C is also known as phosphoinositidase and as polyphosphoinositide phosphodiesterase. Both DAG and IP3 are second messengers. DAG activates protein kinase C, which is important in controlling cell division and cell proliferation. IP3 opens calcium channels and allows the rapid release of the calcium stores in endoplasmic reticulum (in smooth muscle, sarcoplasmic reticulum). The elevated levels of calcium ion stimulate smooth-muscle contraction, exocytosis, and glycogen breakdown. 

Prior to the recent work by Chang and Rapoport. the most widely accepted hypothesis of the mechanism of action of lithium was that it interfered with the PLC-inositol cycle by blocking inositol phosphatase and thus preventing the completion of the cycle by the regeneration of phosphatidyl-inositol. This effect undoubtedly occurs, but doubt has been cast on its relevance because it only does so at concentrations that are considerably higher than those required to inhibit CPLA2. 

Figure 7, Phospholipase C-mediated hydrolysis of phosphatidyl inositol 4,5-bisphos-phate. Phosphoinositide-specific phospholipase C is activated during cellular stimulation and mediates the hydrolysis of phosphatidylinositol 4,5-bisphosphate. The two products of this reaction, DAG and IP3, are both intracellular second messengers. Thus, a single hydrolytic reaction initiates a bifurcating pathway of signal transduction mediated by protein kinase C activation and calcium mobilization, respectively.

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