PI3KAKTmTORWeg

The PI3KAKTmTOR Weg, commonly referred to as the PI3K-AKT-mTOR pathway, is a central intracellular signaling cascade that interprets signals from growth factors, nutrients, and energy status to regulate cell growth, proliferation, survival, metabolism, and autophagy. It is highly conserved across eukaryotes and interacts with multiple other signaling networks.

Core components: Receptor tyrosine kinases or G protein–coupled receptors activate class I PI3Ks, which convert PIP2 to PIP3 at the plasma membrane. PIP3 serves as a docking site for AKT and PDK1; PDK1 phosphorylates AKT at Thr308 and mTORC2 contributes Ser473 phosphorylation, yielding full AKT activation. Active AKT phosphorylates many substrates, including TSC2, leading to activation of mTORC1. PTEN negatively regulates the pathway by dephosphorylating PIP3 back to PIP2.

mTOR functions in two complexes: mTORC1 and mTORC2. mTORC1 regulates protein synthesis and cell growth through S6K1 and 4E-BP1 and is inhibited by rapamycin. mTORC2 phosphorylates AKT on Ser473 and influences cytoskeletal organization and cell survival. The pathway integrates nutrient status and energy signals through AMPK and other sensors.

Physiological roles: in development, metabolism, and immune function. Dysregulation is common in cancers and metabolic disorders; hyperactivation promotes growth and survival, whereas insufficient signaling impairs cell function. The pathway crosstalks with insulin signaling and autophagy pathways, contributing to diseases such as cancer, diabetes, and aging.

Therapeutic targeting and research: inhibitors target PI3K enzymes, AKT, or mTOR complexes (for example, PI3K inhibitors like alpelisib; AKT inhibitors like ipatasertib; mTOR inhibitors such as everolimus, temsirolimus). Resistance and feedback mechanisms pose challenges, and combination therapies are actively explored.