PI3KAktmTORSignalkette

The PI3KAktmTORSignalkette, also referred to as the PI3K-AKT-mTOR signaling pathway, is a central regulator of cell growth, metabolism, and survival that integrates signals from growth factors, nutrients, and energy status. Activation begins when receptor tyrosine kinases or other receptors stimulate phosphoinositide 3-kinases (PI3Ks), which convert PIP2 to the lipid second messenger PIP3 at the inner membrane. PIP3 recruits AKT and its activating kinase PDK1 to the membrane, where AKT is phosphorylated and partly activated; full activation also requires phosphorylation by mTOR complex 2 (mTORC2). Active AKT phosphorylates multiple substrates, including TSC2, relieving inhibition of the small GTPase Rheb and leading to activation of the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 promotes protein synthesis and growth by phosphorylating S6 kinase and 4E-BP1. In parallel, mTORC2 regulates cytoskeletal organization and can contribute to AKT activation, creating a feed-forward loop.

Negative regulation is provided by PTEN, a phosphatase that dephosphorylates PIP3 back to PIP2, thereby attenuating the signal. Nutrient and energy status modulate the pathway through amino acid sensing via Rag GTPases and energy sensing via AMPK; feedback by S6K1 can dampen upstream signaling. The pathway intersects with other signaling cascades, notably the MAPK pathway, and is subject to complex regulation in various cellular contexts.

Physiological roles include control of cell growth, proliferation, metabolism, and autophagy. Dysregulation is common in diseases such as cancer, insulin resistance, and tuberous sclerosis complex. Therapeutic strategies target components of the pathway with PI3K inhibitors, AKT inhibitors, and mTOR inhibitors, though resistance and feedback mechanisms present clinical challenges.