PI3K-PKB/Akt pathway.

Identification of the phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt) pathway and activating receptor tyrosine kinases (RTKs) began in earnest in the early 1980s through vigorous attempts to characterize insulin receptor signaling (for review, see Alessi 2001; Brazil and Hemmings 2001). These humble beginnings led to the identification of the components and mechanism of insulin receptor signaling via insulin receptor substrate (IRS) proteins to PI3K and consequent PKB/Akt-mediated activation by 3-phosphoinositide-dependent protein kinase 1 (PDK1). With the discovery of the potent contribution of PI3K and PKB/Akt activation to tumorigenesis, intense research into the regulation of this pathway led to the discovery of the negative regulators, the protein phosphatase 2 (PP2A), phosphatase and tensin homolog (PTEN), and the PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2). More recently, the elusive PKB/ Akt hydrophobic motif kinases—i.e., the mammalian target of rapamycin (mTOR), when associated with the mTOR complex 2 (mTORC2), and the DNA-dependent protein kinase (DNA-PK)—were identified, as was the ability of Ras to affect the PI3K-PKB/Akt pathway via PI3K, completing our current model of the PI3K-PKB/Akt pathway. The PI3K-PKB/Akt pathway is highly conserved, and its activation is tightly controlled via a multistep process (as shown in Fig. 1) Activated receptors directly stimulate class 1A PI3Ks bound via their regulatory subunit or adapter molecules such as the insulin receptor substrate (IRS) proteins. This triggers activation of PI3K and conversion by its catalytic domain of phosphatidylinositol (3,4)-bisphosphate (PIP2) lipids to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PKB/Akt binds to PIP3 at the plasma membrane, allowing PDK1 to access and phosphorylate