PI3-Kinases

Another type of NR crosstalk, which has only recently been recognized, is the so-called nongenomic actions of several receptors that induce very rapid cellular effects. Effectively, evidence has accumulated over several decades that steroid receptors may have a role that does not require their transcriptional activation, such as modifying the activity of enzymes and ion channels. While the effects of steroids that are mediated by the modulation of gene expression do occur with a time lag of hours, steroids can induce an increase in several second messengers such as inositol triphosphate, cAMP, Ca2+, and the activation of MARK and PI3 kinase within seconds or minutes. Many mechanistic details of these nongenomic phenomena remain poorly understood. Notably, controversy still exists as to the identity of the receptors that initiate the non-genomic steroid actions. However, it now appears that at least some of the reported effects can be attributed to the same steroid receptors that are known as NRs. 

Among the substrates of Src are other nonreceptor PTKs (e.g., Fak, Syk, and Tec kinases), RTKs (e.g. EGF and PDGF receptors), phospholipase Cy, PI3-kinase, phosphatases (e.g., SHP-2 and PP2A), and adaptor (e.g., She and Cbl) as well as focal adhesion proteins (e.g., paxillin, pl30Cas andtensin). Src-mediated phosphorylation either modulates enzymatic activity of... 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

FIGURE 8.8 Mechanism of activation of protein kinase B (PKB). PI3-kinase is recruited to the membrane via direct association with the receptor PTK or via association with the docking protein Gab-1. It catalyzes the generation of phosphatidyl-3,4,5-inositolphosphate, which serves as a membrane-recruitment signal for PKB. Associated with the membrane, it is first phosphorylated in its catalytic domain by PDK1 and then by PDK2 in the hydrophobic motif. The activated PKB then detaches from the membrane. 

PI3K p85B PI3-kinase family, p85-binding domain E(M) 0(0) 0(0) ... 

Cao, P. Maira, SM., Garcia-Echeverria, C. and Hedley, DW. (2009) Br. J. Cancer, Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xengrafts. 100, 1267-1276. 

Failla M, To Y, Ito M, Adcock IM, Barnes PJ, Ito K. (2007) Oxidative stress-induced PI3-kinase activation reduces HDAC activity and is inhibited by theophylline. Proc Am Thorac Soc 2 A45 (Abstr.)... 

PI3-kinase/Akt-3 Phosphoinositide-3-kinase/serine-threonine kinase Akt-3 PGGT Protein geranylgeranyl transferase... 

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