Signal transduction phosphoinositide activation

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.

Most G proteins are heterotrimers consisting of a, P and y subunits which function in close association with several transmembrane receptors. Their activity is regulated by the binding of GTP to the a subunit, followed by subsequent hydrolysis of GTP to GDP, and release of GDP (41). Functions regulated by G proteins include stimulation of phosphoinositide hydrolysis, modulation of adenylate cyclase activity and activity of ion channels (41). Therefore, G proteins play a crucial role in relaying information from cell surface receptors to the intracellular signal-transduction machinery. 

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