Signal transduction AKT signaling
AKT signaling RAC-alpha serine/threonine kinases ( AKTs ) are crucial mediators of variouscellular process, such as apoptosis, regulation of cell cycle, protein synthesis andregulation of metabolism. The activity of AKT is modulated by various proteins,including Phosphatidylinositol-3-kinase ( PI3K ), Phosphoinositide-dependentkinase 1 ( PDK ), phosphotases PTEN, PP2A, and heat-shock protein( Hsp90). PI3K converts phosphatidylinositol 4,5-biphosphate ( PI(4,5)P2 ) to phosphatidylinositol 3,4,5-triphosphate ( PI(3,4,5)P3 ), which is secondary messenger involved the in regulation of variousprocess . PI(3,4,5)P 3 associates with the inner lipidbilayer of the plasma membrane and promotesthe recruitment of proteins with pleckstrinhomology (PH) domains such as AKT and PDK. Upon binding to the membraneAKT and PDK became active. Notably, translocation of AKT to theplasma membrane also facilitates its phosphorylation by PDK . AKT activity can be inhibited indirectly though the t phosphatase PTENthat cleaves the 3' phosphate from PI(3,4,5)P 3 to generate PI(4,5)P2. PTEN therefore, acts to decrease levels of PI(3,4,5)P3 causing an antagonistic effect of AKT -inducedcell survival . The phosphatase PP2A dephosphorylates and inhibits AKT directly and thisis counteracted by Hsp90. Hsp90 forms a complex with AKT and preventsPP2A -mediated dephosphorylation. Hsp90 plays an important role inmaintaining AKT kinase activity . Activated AKT prevents cells from undergoing apoptosis by inhibitingproapoptotic proteins BCL2-associated agonist of cell death ( BAD ) andCaspase-9 . AKT induces phosphorylation of BAD,preventing BAD from binding with anti-apoptotic factor BCL2-like 1 ( BCL-X) therby reducing antiapoptotic events . AKT can interfere with cell death via a member of the forkhead family oftranscription factors (e.g., Forkhead box O3 ( FOXO3A), which is a direct targetfor phosphorylation by AKT). FOXO3A has been implicated in the expressionof the FAS ligand ( FasL ) and the Bcl-2 interacting mediator of cell death (Bim ), which can induce cell death. Upon phosphorylation by AKT,FOXO3A is retained in the cytosol preventing transcriptional regulation andexpression of FasL and Bim in the nuclease, allowing the cell survival. AKT also regulates the activity of other transcription factors, such as nuclearfactor-kappaB ( NF-kB ), Tumor protein p53 ( p53 ), c-Myc. AKTphosphorilates and activates I-kB kinase ( IKK ), that regulate the activity ofthe NF-kB transcription factor. When bound to its cytosolic inhibitor I-kB, NF-kB is inactive. Upon phosphorylation of I-kB by IKK, theinhibitor is degraded, allowing NF-kB to move to the nucleus and activate thetranscription of antiapoptotic proteins . AKT phosphorylates ubiquitin-protein ligase E3 Mdm2 p53 binding protein homolog( MDM2 ) that results in its translocation into the nucleus where it binds totranscription factor p53. p53 mediates apoptosis through transactivationof apoptotic activator BAX . MDM2 interacts with thep53, inhibits its transcriptional activity and targets it for degradation by theproteasome . AKT affects the cell cycle progression by regulating the Cyclin Dfunction. This is accomplished by phosphorylation of Cyclin-dependent kinase inhibitor 1A( p21/WAF1) by AKT. This result to cytoplasmic localization ofp21/WAF1, thereby preventing its function in the nucleus. In the nucleous, theprotein p21/WAF1 interacts with and inhibits the essential DNA replication factor,proliferating-cell nuclear antigen ( PCNA ). p21/WAF1 and PCNA formscomplex with Cyclin D . Another target for AKT is Glycogen synthase kinase 3 ( GSK3 ), whichnegativly regulates glycogen synthesis and cell cycle progression via inhibitoryphosphorylation of glycogen synthase and transcription factors c-Myc and CyclinD, respectively. Additionally, FOXO3A has been implicated in expression of the C yclin-dependentkinase inhibitor 1B ( P27KIP1 ), which binds with and inhibits Cyclin D . The activation of AKT results in the stimulation of protein synthesis viaactivation of Ribosomal protein S6 kinase ( p70S6K ). The activation ofp70S6K by AKT occurs via direct and indirect mechanisms. The indirectprocess is mediated by FKBP-rapamycin associated protein ( FRAP1 ). In absence ofAKT -mediated phosphorylation, Tuberin via the small GTPase Rhebinhibits FRAP1, allowing the activation of P70S6K the leads to multiplephosphorylation events of 40S ribosomal protein S6 ( RPS6 ) to trigger proteinsynthesis .