Phosphoinositide 3-kinase and mechanistic target of rapamycin complex 1 and 2 (PI3K, mTORC1, mTORC2)

The phosphoinositide 3-kinase (PI3K)–mechanistic target of rapamycin (mTOR) pathway is a central intracellular signaling axis regulating cell growth, proliferation, metabolism, and survival. PI3K, a lipid kinase, generates PIP3 which activates downstream targets including Akt. mTOR functions as the core kinase within two complexes: mTORC1 and mTORC2. mTORC1, composed of mTOR, Raptor, mLST8, PRAS40, and DEPTOR, integrates signals from nutrients and growth factors to stimulate anabolic processes and inhibit autophagy. mTORC2, with mTOR, Rictor, mLST8, mSIN1, Protor, and DEPTOR, regulates AGC kinases like Akt and is crucial for cytoskeletal organization and cell survival. Dysregulation of this signaling network is a hallmark of cancer and other diseases. Therapeutic targeting includes specific and dual inhibitors of PI3K, mTORC1, and mTORC2, but is challenged by feedback loops, pathway crosstalk, toxicity, and compensatory resistance mechanisms.

Other names

Phosphoinositide 3-kinasephosphatidylinositol 3-kinaseMechanistic target of rapamycinmammalian target of rapamycinMechanistic target of rapamycin complex 1Mechanistic target of rapamycin complex 2FRAP (FKBP-rapamycin associated protein)mLST8 (shared complex component, aka GβL)Raptor (mTORC1 subunit)Rictor (mTORC2 subunit)mSIN1 (mTORC2 subunit)PRAS40 (inhibitory mTORC1 subunit)DEPTOR (shared inhibitor)

PI3K inhibitors prevent generation of PIP3, halting downstream activation of Akt and mTOR. mTORC1 inhibitors block phosphorylation of effectors such as S6K and 4E-BP1, disrupting protein synthesis and cell growth. mTORC2 inhibitors block activation of AGC kinase family members, importantly AKT (Ser473), impacting cell survival signal transduction. Dual inhibitors block both PI3K and mTORC1/2, leading to broader pathway inhibition.