PKB, Protein kinase B

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. 

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) ... 

An application of this synthetic strategy by the same group led to the development of a series of potent and selective allosteric Akt (protein kinase B/PKB) kinase inhibitors that induced apoptosis in tumor cells and inhibited Akt phosphorylation in vivo (Scheme 6.261) [451]. 

Abelson leukemia virus tyrosine kinase Protein kinase B (PKB)... 

Protein kinase B (PKB), which is also known as Akt, is a serine/threonine kinase that also belongs to the AGC kinase subtype. Three mammalian isoforms—PKBo , /3, and y have been identified. These proteins are broadly expressed and, although isoform-specific patterns of expression exists in some tissues, the three kinases have a similar organizational structure an amino-terminal PH domain, a central serine/threonine catalytic domain, and a short regulatory region at the carboxy terminal end containing the so-called hydrophobic motif [118-120]. 

The PI3 kinase (PI3-K) is translocated to the membrane by interaction of the SH2 domain of its p85 subunit with phosphotyrosine residues of the activated receptor. There it converts PtdIns(3,4)P2.into PtdIns(3,4,5)P3 which binds to PH domains of various effector molecules and recruits them into the signaling chain. The effector molecules can stimulate cell division or can induce the programmed cell death. The tumor suppressor PTEN hydrolyses phosphates from PtdIns(3,4,5)P3 and thus inhibits the growth promoting effect of the PI3 kinase signaling. An important effector of PI3 kinase is the protein kinase Akt which is also termed protein kinase B (PKB). GF growth factor GFR growth factor receptor. 

An important target protein of Ptdlns(3,4,5)P3 is Akt kinase, also known as protein kinase B (PKB). The signahng pathway for Akt kinase shown in Fig. 6.9b illustrates the role of P13-kinase and Ptdlns(3,4,5)P3 in growth factor controlled signal pathways that lead from the cell membrane into the cytosol and the nucleus. 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

Paramio, J. M., Segrelles, C., Ruiz, S., and Jorcano, J. L. (2001). Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin KlO-induced cell cycle arrest. Mol. Cell. Biol. 21, 7449-7459. 

NGF (Kaplan and Miller, 2000). PI3-K generates 3 -phosphorylated phosphoi-nositides that, in turn, activates Akt, also known as protein kinase B (PKB), a serine/threonine kinase with prosurvival and antiapoptotic activities (Franke et al., 2003). 

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