Pathways

Akt (v-Akt Murine Thymoma Viral Oncogene) is a serine kinase that is involved in mediating various biological responses, such as inhibition of apoptosis and stimulation of cell proliferation. Activation of Akt can begin with several events, mainly the binding of a ligand to a receptor in the cell membrane. Most common ligands activating Akt include growth factors, cytokines, mitogens and hormones. The actions of Akt in the cell are numerous and diverse, but all result in anti-apoptosis, or pro-cell proliferation effects. These physiological roles of Akt include involvement in metabolism, protein synthesis, apoptosis pathways, transcription factor regulation and the cell cycle. The downstream targets of Akt include BAD (BCL2 Antagonist of Cell Death), Caspase-9, FKHRL (Forkhead Transcriptional Factor), IKK (I-KappaB Kinase), and mTOR (Mammalian Target of Rapamycin). Akt inhibits apoptosis by phosphorylating the BAD component of the BAD/BclXL (Bcl2 Related Protein Long Isoform) complex. Phosphorylated BAD binds to 14-3-3, causing dissociation of the BAD/BclXL complex and allowing cell survival. Akt activates IKK, which ultimately leads to NF-KappaB activation and cell survival. Other direct targets of Akt are members of the FKHRL. In the presence of survival factors, Akt1 phosphorylates FKHRL1, leading to the association of FKHRL1 with 14-3-3 proteins and its retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation and target gene activation. Within the nucleus, FKHRL1 most likely triggers apoptosis by inducing the expression of genes that are critical for cell death, such as the Fas ligand (TNF superfamily, member 6) gene. Another notable substrate of Akt is the protease Caspase-9. Phosphorylation of Caspase-9 decreases apoptosis by directly inhibiting the protease activity. Akt may also be involved in activation of the nutrient-dependent Thr/Ser kinase, mTOR.