Signal transduction phosphoinositide 3-kinase

Corvera, S. and Czech, M. R, Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction [review], Trends Cell. Biol., 8, 442-6, 1998. 

Developmental exposure to Pb or Mm affect signal transduction process, possibly related to the modulation of nitric oxide as well as alterations in receptor-mediated phosphoinositide hydrolysis and protein kinase C (rats)... 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

Efferth T, Volm M (1992) Expression of protein kinase C in human renal cell cardnoma cells with inherent resistance to doxorubicin. Anticancer Res 12 2209-2211 Eguchi Y, Srinivasan A, Tomaselli KJ, Shimizu S, Tsujimoto Y (1999) ATP-dependent steps in apoptotic signal transduction. Cancer Res 59 2174-2181 Ek TP, Campbell MD, Deth RC, Gowraganahalli J (1989) Reduction of norepinephrine-induced tonic contraction and phosphoinositide turnover in arteries of spontaneously hypertensive rats. A possible role for protein kinase C. Am J Hy-pertens 2 40-45... 

MacDougall, E.K. Domin, J. Waterfield, M.D. A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction. Curr. Biol., 5, 1404-1415 (1995)... 

McNamara R. K., Ostrander M., Abplanalp W., Richtand N. M., Benoit S. C., and Clegg D. J. (2006). Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids Implications for the pathophysiology and treatment of recurrent neuropsychiatric illness. Prostaglandins Leukot. Essent. Fatty Acids 75 237-257. 

Activation of the chemokine receptor leads to rapid activation of phosphoinositide-spe-cific phospholipases, which leads to inositol-1,4,5-triphosphate formation and a transient rise in intracellular calcium (18). Phospholipase C (PLC) isoforms that are involved in chemokine receptor activation become activated by direct interaction with the J3y subunits. In addition to its interaction with PLCs, the j3y subunits also interact with the type phosphoinositol 3 kinase y (PISKy), and activation of this enzyme results in the formation of PtdIns(3,4,5)P3 (17). Mice that do not express PI3Ky have severely impaired chemo-kine-stimulated signal transduction, and PKB is not activated, suggesting an important role for this pathway in the chemotactic process (27-29). Although leukocytes isolated from these mice showed a decrease in cell chemo-taxis, the response is not completely lost, and under conditions of complete PI3Ky inhibition, neutrophils can still chemotax in response to chemokines (30). 

Figure 14.20 Insulin signaling. The binding of insulin results in the cross-phosphorylation and activation of the insulin receptor. Phosphorylated sites on the receptor act as binding sites for [insulini receptor substrates such as IRS-1. The lipid kinase phosphoinositide 3-kinase binds to phosphorylated sites on IRS-1 through its regulatory domain, then converts PIPj into PIPv Binding to PiP activates PIP3-dependent protein kinase, which phosphorylates and activates kinases such as Aktl. Activated Aktl can then diffuse throughout the cell to continue the signal-transduction palhway.

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.

PI is involved in membrane anchoring of proteins via GPI and the inositol moiety is a substrate for lipid kinases yielding phosphoinositides involved in cytoskeletal organization, vesicle transport and signal transduction. 

In previous sections, we have seen how signal transduction from cytokine receptors and receptor tyrosine kinases (RTKs) begins with formation of multiprotein complexes associated with the plasma membrane. Here we discuss how these receptors initiate signaling pathways that Involve membrane-bound phosphorylated inositol lipids, collectively referred to as phosphoinositides. We begin with the branch of the phospholnositide pathway that also is mediated by G protein-coupled receptors and then consider another branch that is not shared with these receptors. 

Preliminary data further suggest the involvement of phosphoinositides in G A3-induced synthesis and secretion of a-amylase in aleurone cells [13]. GA3 activation of protein kinase C-like enzyme has been shown in potato tubers [10]. The in vitro effect of 2,4-D on protein phosphorylation in a membrane fraction isolated from etiolated soybean hypocotyls may also be associated with this system [24]. Further investigation in this field may be valuable in the elucidation of molecular mechanism of phytohormone signal transduction and amplification. 

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