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Abstract
Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBα/Akt1, PKBβ/Akt2 and PKBγ/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.
Keywords: Akt/PKB * protein phosphorylation * cell survival * apoptosis
* Introduction
* Structural features of Akt/PKB protein kinases
* Regulation of Akt/PKB activity
*Phosphoinositide 3-kinase (PI3-Kinase) dependent activation of Akt/PKB
* Membrane translocation
* Phosphorylation of Akt/PKB
* Phosphorylation of Thr308
* Phosphorylation of Ser473
* Phosphorylation of tyrosine residues
*Phosphoinositide 3-kinase (PI3-Kinase) independent activation of Akt/PKB
*Proteins bind and regulate Akt/PKB
* Regulation of cell survival by Akt/PKB
*Direct regulation of cell survival
* BAD
* Caspase-9
* SAPK
*Transcriptional control of cell survival
* FoxO Forkhead
* NF-κB
* Mdm2
* CREB
* YAP
*Metabolic regulation of cell survival
* Conclusions
Introduction
Akt/PKB protein kinase, a serine/threonine kinase, belongs to the cAMP-dependent protein kinase A/ protein kinase G/ protein kinase C (AGC) super family of protein kinases that share structural homology within their catalytic domain and have the similar mechanism of activation. Deregulations of some of these kinases are frequently associated with human diseases including cancer and diabetes [1,2]. Akt/PKB was initially identified by three independent groups, based on its homology to protein kinase A (PKA) [3] and C (PKC) [4] or as the cellular homolog to the retroviral oncogene viral akt (v-Akt) [5]. In mammals, three Akt/PKB genes have been identified, termed PKBα/Aktl [6], PKBβ/Akt2 [7] and PKBy/Akt3 [8], located at chromosomes 14q32, 19ql3, and Iq44, respectively.
Over the past decade, Akt/PKB has emerged as a central player in the signal transduction pathways activated in response to growth factors or insulin and is thought to contribute to several...