Akt

Akt

Akt, or protein kinase B (PKB), is a Ser/Thr protein kinase that phosphorylates a variety of protein substrates to regulate numerous cellular functions. Such as protein synthesis, metabolism, transcription, cellular proliferation, cellular differentiation, migration, and apoptosis (programmed cell death).

Akt, or protein kinase B (PKB), is a Ser/Thr protein kinase that phosphorylates a variety of protein substrates to regulate numerous cellular functions. Such as protein synthesis, metabolism, transcription, cellular proliferation, cellular differentiation, migration, and apoptosis (programmed cell death) . , IκB , Rac, Rho, p70S6kinase, Caspase 9, from benign to malignant states, as well as metathesis. Overall, Akt activation down-regulates the expression of proapoptotic proteins and upregulates the expression of antiapoptotic proteins. Akt has gained significant attention in the last two decades as it is suggested to be the only protein kinase that consistently exhibits antiapoptotic activity in numerous biological systems.

Metabolism Signaling Pathway

The first cellular substrate identified for Akt was glycogen synthase kinase 3 (GSK3),which plays a key role in metabolism and insulin signaling pathways. Akt negatively regulates GSK3 via insulin stimulated phosphorylation of the enzyme at Ser21 (GSK3α) or Ser9 (GSK3β). Ser9 of GSK3β was shown to be conserved in vertebrates and to have higher affinity for Akt when compared to other protein kinases, demonstrating GSK3 to be an in vivo substrate of Akt. The phosphorylation event on GSK3 results in the inactivation of the enzyme and consequent activation of glycogen synthase, thereby leading to increased glycogen storage in muscle tissue. In addition, GSK3 inactivation by means of phosphorylation by Akt has been shown to protect the cell from apoptosis. GSK3 is engaged in several other signaling transduction pathways including the regulation of API and the cyclic AMP response element binding protein (CREB) transcription factors as well as the adenomatous polyposis coli (APC) tumor suppressor gene. Besides GSK3 phosphorylation, Akt plays additional roles in metabolic pathways such as stimulation of glycolysis via recruitment of GLUT4 glucose transporters to the plasma and direct control of the activity of phosphofructo-kinase.

Protein Synthesis and Cell Growth Signaling Pathways

Several transcription factors are regulated by Akt, which enhances mRNA translation and protein synthesis, important factors in the control of cell growth. Phosphorylation of a translation repressor, binding protein 4E-BP, by Akt leads to the subsequent activation of translation initiation factor eIF-4E, which induces mRNA translation. Akt may also regulate the activity of mTOR/FRAP, which leads to the activation and elongation of translation through the phosphorylation of 4E-BP and up-regulation of p70 S6 kinase and elongation factor eEF2. Phosphorylation of GSK3 by Akt could also lead to the activation of translation initiation factor eIF2B, thus increasing mRNA translation.Akt induces cellular growth by phosphorylating several substrates involved in the regulation of the cell cycle. Akt phosphorylates various nuclear targets including transcription factors of the Forkhead family such as FKHRL1 (FOXO3a), which in its active form induces cell cycle arrest and apoptosis. Akt inactivates the transcription factor via phosphorylation at Ser253, resulting in translocation of FKHRL1 from the nucleus to the cytoplasm. This translocation allows for the FKHRL1 target genes to be shutoff consequently promoting cell cycle progression and survival. Another member of the Forkhead family that is inactivated through phosphorylation by Akt is the transcription factor AFX. Active AFX up-regulates cell cycle inhibitor p27kipl and as a result induces cell cycle arrest at the G1 phase. Akt regulates AFX through phosphorylation and consequent inactivation of the transcription factor, thereby allowing the cells to proceed into the S phase through the reduction of p27kipl levels. Modification of Forkhead transcription factors FKHRL1 and AFX by Akt also results in the down-regulation of proapoptotic proteins including the Fas ligand of the tumor necrosis factor (TNF) family.

Reference:Substrate-M imetic Inhibitors of Akt as Potential Anti-Cancer Therapeutics. Katherine J. Kayser

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