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Pathway description:
Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-B) is a Serine/threonine Kinase that is involved in mediating various biological responses, by phospho-rylation of a number of intracellular proteins, regulates different cellular processes, such as cell growth, cell cycle, apoptosis and glucose metabolism. Akt is activated by several hormones including insulin, growth factors, by signals derived from receptors for extracellular matrix molecules such as integrins, by several forms of cellular stress such as oxidative stress or cell swelling, and by activation of Ras. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/ PKB-Gamma. All three isoforms of Akt share a common structure of three domains. Activation of PI3K by receptor tyrosine kinases mediates the phosphorylation of PIP2 to PIP3 and thereby the recruitment of Akt/PKB and PDK to the plasma membrane. Akt/PKB is subsequently activated and phosphorylation at Thr308 by PDK. PIP3 at the cell membrane recruits protein kinases such as Akt/PKB and PDK.PTEN functions as an antagonist of PI3K.PDK further activates SGK and aPKC , aPKC and SGK in turn phosphorylate a wide variety of cellular signaling molecules relevant for the regulation of cell growth, cell cycle and cell proliferation, including FKHR, GSK3, mTOR and p70S6K, for apoptosis, including Bad, caspase 9, IκB, FKHR, Mdm2. Akt/PKB further activates mTOR, a kinase stimulating the uptake of nutrients such as glucose, amino acids, cholesterol and iron. mTOR regulates the phosphorylation of p70S6K which can similarly be activated by PDK. mTOR further activates eIF4E-binding protein-1 and thus is involved in the regulation of translation.
Selected Reviews:
Wang Q,Liu L,et al.(2003)Control of synaptic strength,a novel function of Akt.Neuron.38(6),915.
Basso Ade, Solit DB,et al.(2002)Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function.J Biol Chem.277(2),39858.
Fornaro M,Plescia J,et al.(2003)Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem.278(50),50402.
Pommery N,Henichart JP.(2005)Involvement of PI3K/Akt pathway in prostate cancer –potential strategies for developing targeted therapies.Mini Rev Med Chem.5(12),1125
