PTEN mRNA translation negatively regulated by microRNAs MIR26A microRNAs bind PTEN mRNA PDPK1 binds PIP2 AKT binds PDPK1 PIP3 recruits PDPK1 to the membrane TORC2 (mTOR) phosphorylates AKT at S473 PIP3 recruits AKT to the membrane PI3K phosphorylates PIP2 to PIP3 AKT translocates to the nucleus PDPK1 phosphorylates AKT at T308 AKT phosphorylates targets in the cytosol PIP3 activates AKT signaling Pubmed17604717 Reactome Database ID Release 431257604 Reactome, http://www.reactome.org ReactomeREACT_75829 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. Negative regulation of the PI3K/AKT network AKT phosphorylates targets in the nucleus PathwayStep3895 PathwayStep3896 PathwayStep3871 PathwayStep3872 PathwayStep3870 PathwayStep3869 PathwayStep3893 PathwayStep3894 PathwayStep3884 PathwayStep3889 PathwayStep3883 PathwayStep3874 PathwayStep3873