PI-3-kinase pathway

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway, in particular, effects mediated through its effector protein kinase B (PKB, also termed Akt three isoforms) ... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Parsons, R., 2004, Human cancer, PTEN and the PI-3 kinase pathway. Sem. Cell Dev. Biol. 15 171-176. 

Xia M, Hyman BT (2002) GROalpha/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERKl/2 and PI-3 kinase pathways and for tan hyperphosphorylation-a role in Alzheimer s disease J Neuroimmunol 122 55-64. 

Signal transduction (1) Ras-MAP kinase pathway (2) IP3/DAG pathway (3) PI-3 kinase pathway... 

In addition to initiating the IP3/DAG pathway, some activated RTKs and cytokine receptors can initiate another phospholnositide pathway, the PI 3 kinase pathway, by re... 

A FIGURE 14-27 Recruitment and activation of protein kinase B (PKB) in PI-3 kinase pathways. In... 

The Insulin Receptor Acts Through the PI-3 Kinase Pathway to Lower Blood Glucose... 

PTEN Phosphatase Terminates Signaling via the PI-3 Kinase Pathway... 

PI-3 kinase pathway 598 presenllln 1 603 protein kinase B 599 PTEN phosphatase 600 Ras protein 587 receptor tyrosine kinases 578 regulated intramembrane proteolysis 603 scaffold proteins 597 SH2 domains 579 Smads 575... 

EXAMPLE 6.29 Mutant forms of Ras are commonly found in human cancers. In some cases the mutations are in the GTPase active site of Ras, which makes it unable to hydrolyze GTP. The overall effect is that the mutant Ras is locked into a permanently active form this leads to uncontrolled signaling down the MAP kinase and PI-3-kinase pathways, contributing to uncontrolled cell proliferation. 

Starkman, B. G., Cravero, J. D., Delcarlo Jr, M., and Loeser, R. E 2005. lGF-1 stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochemical Journal, 389, 723. 

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