The PI3K/Akt/mTOR Pathway

Identification of the phosphatidylinositol 3'-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) pathway began in the mid-1980s. Since its discovery, interest among the scientific community and the quantity of research done in this pathway have been remarkable. Over the last 20 years, an enormous amount of evidence has demonstrated that PI3K/ Akt/mTOR is a key signaling pathway involved in many physiological and pathophysiological processes. In 1988, Cantley and colleagues identified a phosphatidylinositol (PtdIns) 3-kinase able to phosphorylate the 3-OH group of the inositol ring of PtdIns in vitro, yielding the PtdIns- 3,4,5-trisphosphate (PtdIns3,4,5P3). Scientific attention to this pathway increased in 1991 through the development of a natural product with antifungal and immunosuppressive activity derived from the bacterium Streptomyces hygroscopicus. This compound, called rapamycin (or sirolimus), showed inhibitory activity against mTOR. Following studies discovered several functions of mTOR in higher eukaryotes, making this protein kinase to gain its central position in the signaling network that regulates cell growth and survival. In 1991, three independent groups discovered a gene that encoded a serine/threonine (Ser/Thr) kinase, corresponding to Akt. Four years later, two independent groups highlighted that Akt was activated by growth factors in a PI3Kdependent manner. The exact mechanism of this phospho-regulation was demonstrated in 1996 by Alessi and colleagues, who showed that activation of Akt required a double phosphorylation event on residues Thr 308 and Ser 473. A year later, the same group identified a specific kinase that phosphorylated the Thr 308 residue, which they referred to as phosphoinositidedependent kinase 1 (PDK1). Then, in 2005, an mTOR complex 2 (mTORC2) was identified as the kinase complex that phosphorylates the other amino acidic residue necessary for full Akt activation.