Protein kinase B

Forino M, Jung D, Easton JB, Houghton PJ, Pellecchia M. Virtual docking approaches to protein kinase B inhibition. J Med Chem 2005 48 2278-81. 

Tilton B, Ho L, Oberlin E, et al. Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med 2000 192(3) 313-324. 

Protein kinase B, or Akt, was discovered as the product of an oncogene of the acutely transforming retrovirus AKT8, causing T-cell lymphomas in mice. It encodes a fusion product of a cellular serine/threonine protein kinase and the viral structural protein Gag. This kinase is similar to both protein kinase Ce (PKCe 73% identity to the catalytic domain) and protein kinase A (PKA 68%). It differs from other protein kinases in that it contains a pleckstrin homology (PH) domain, which allows it to bind to polyphosphoinositide head groups (and also to G-protein fly subunits). To date, three subtypes have been identified a, (3, and y, all of which show a broad tissue distribution. It... 

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. 

Brognard, J., Clark, A.S., Ni, Y., and Dennis. P.A. 2001. Akt/protein kinase b is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. 

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) ... 

Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. (2000). The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independendy ofp38 mitogen-activated protein kinase. J. Biol. Chem. 275, 7395-7402. 

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]. 

FOXOS, protein kinase B-regulated Forkhead transcription factor... 

Akama, K. T. and McEwen, B. S. Estrogen stimulates post-synaptic density-95 rapid protein synthesis via the Akt/ protein kinase B pathway. /. Neurosci. 23 2333-2339,2003. 

AKT-1 kinase (also called protein kinase B or PKBa) is a serine/threonine kinase belonging to the AGC kinase family [1], AKT was identified from a viral oncogene, v-akt, found in tumor lines established from spontaneous thymomas found in AKR mice [2]. Subsequently, two more AKT isoforms, AKT-2 (or PKB(3) and AKT-3 (or PKBy) have been identified [3]. Reviews exist detailing the structural and cell biology of AKT and the reader is referred to these for further information [4,7,12]. 

Anderson, K.E., CoadweU, J., Stephens, L.R., and Hawkins, P.T., 1998, Translocation of PDKl to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr. Biol, 8 684-691. 

Carson, J.P., KuUk, G., Weber, M.J. 1999, Antiapoptotic signaling in LNCaP prostate cancer cells a survival signaling pathway independent of phosphatidylinositol 3 -kinase and Akt/protein kinase B. Cancer Res Apr 59 1449-1453... 

Persad, S., AttweU, S. Gray, V., Delcomenne, M., Troussard, A., Sanghera, J., and Dedhar, S., 2000, Inhibition of integrin-hnked kinase (ILK) suppresses activation of protein kinase B/Akt and induces ceU cycle arrest and apoptosis of PTFN-mutant prostate cancer cells. 

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