Phosphatidylinositol 3-kinase and mechanistic target of rapamycin (PI3K and mTOR)

Phosphatidylinositol 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) are central, interconnected kinases in the PI3K/AKT/mTOR signaling pathway. PI3K is a family of lipid kinases that phosphorylate the 3’ position of phosphoinositides, producing PIP3 and leading to activation of the serine/threonine kinase AKT. AKT then activates mTOR through diverse intermediary proteins, including the TSC1/TSC2 complex and Rheb. mTOR is a serine/threonine kinase that forms two complexes (mTORC1 and mTORC2) and acts downstream of PI3K/AKT signaling to regulate fundamental processes such as cell growth, metabolism, survival, and protein synthesis. Hyperactivation of this signaling axis is one of the most frequent abnormalities in human cancers, making both PI3K and mTOR major therapeutic targets for oncology and potentially other indications where dysregulated cell survival and metabolism occur. Various inhibitors targeting these kinases or the whole pathway are in clinical use or under development. Although often studied together, PI3K and mTOR are distinct molecular enzymes, each with unique structural, biochemical, and regulatory properties, but together they constitute a central node controlling cell fate in health and disease.

Other names

Phosphoinositide 3-kinasePI 3-kinasePI(3)KPI3K catalytic subunitMammalian target of rapamycinFK506-binding protein 12-rapamycin associated protein 1FRAP1Rapamycin and FKBP12 target

PI3K inhibitors: inhibit lipid kinases to block downstream AKT/mTOR signaling. mTOR inhibitors: allosterically or directly inhibit mTOR kinase activity to block cell growth and survival signaling. Dual PI3K/mTOR inhibitors: block both PI3K enzymatic activity and mTOR complex activity.