PI3K/mTOR/AKT Signaling Pathway

Insulin binds to its receptor, an RTK, causing auto-phosphorylation of tyrosine residues on the receptor's cytoplasmic domain. These phosphorylated tyrosines serve as docking sites for insulin receptor substrate (IRS) proteins, which are then phosphorylated. The phosphorylated IRS recruits PI3K to the plasma membrane, initiating the cascade that activates downstream signaling components.

PI3K phosphorylates PIP2 to produce PIP3, which functions as an anchoring site on the plasma membrane. Adjacent PIP3 molecules recruit two key proteins: AKT and PDK1, both containing PH domains that bind to PIP3. This localization positions these proteins for activation and allows the subsequent phosphorylation events that drive the signaling cascade forward.

mTORC2 phosphorylates AKT at serine 473, inducing a conformational change that exposes threonine 308. This exposure allows PDK1 to phosphorylate AKT at this threonine residue, fully activating the kinase. Once activated, AKT dissociates from the membrane to phosphorylate downstream targets that promote cell growth and proliferation.

mTORC1 contains rapamycin-sensitive Raptor and PRAS40 proteins, while mTORC2 contains rapamycin-insensitive Rictor and mSin1. Both complexes share mLST8 as a common component. These structural differences result in distinct functional roles: mTORC1 primarily regulates cell growth, while mTORC2 phosphorylates and activates AKT in response to growth signals.

AKT phosphorylates FOXO3a, a transcription factor that normally activates pro-apoptotic genes. Phosphorylation causes FOXO3a to bind 14-3-3 protein and become sequestered in the cytosol, preventing it from entering the nucleus. This blocks the transcription of pro-apoptotic proteins, thereby promoting cell survival rather than programmed cell death.

Activated AKT inhibits tuberous sclerosis protein 2 (TSC2), which normally suppresses Rheb. By inhibiting TSC2, AKT allows Rheb to remain in its active GTP-bound state. Activated Rheb-GTP then stimulates mTORC1, creating a positive feedback loop that amplifies cell growth signals downstream of the initial insulin stimulus.

The PTB domain on IRS proteins binds to phosphorylated tyrosines on the activated insulin receptor, anchoring IRS to the receptor. The PH domain helps IRS bind phosphoinositides on the plasma membrane, positioning it optimally for phosphorylation and subsequent recruitment of PI3K. This dual-domain architecture ensures efficient signal transmission from the receptor to downstream kinases.