PI3KAKTroutes

PI3KAKTroutes refer to the signaling pathways that couple phosphoinositide 3-kinase (PI3K) activity to AKT kinase signaling, governing cellular growth, survival, and metabolism. Activation typically begins when extracellular signals such as growth factors engage receptor tyrosine kinases or G protein-coupled receptors, activating class I PI3K. PI3K then converts PIP2 to PIP3, which recruits AKT and its activating kinase PDK1 to the plasma membrane. PDK1 phosphorylates AKT at Thr308, while mTORC2 phosphorylates Ser473 to yield full AKT activity.

Activated AKT phosphorylates a wide range of substrates, promoting protein synthesis and cell survival while inhibiting apoptotic pathways. Downstream targets include the TSC2–mTORC1 axis, GSK3, FOXO transcription factors, and PRAS40, leading to increased anabolic metabolism via mTORC1 and S6K/4E-BP1 signaling, changes in glucose handling, and mobilization of nutrient stores. The pathway is subject to feedback regulation and cross-talk with other signaling networks, notably the MAPK pathway and AMPK signaling, and is modulated by the tumor suppressor PTEN, which dephosphorylates PIP3.

Biological importance and disease relevance: The PI3KAKT pathway is essential for development and normal tissue homeostasis. Dysregulation is common in cancer, where PIK3CA mutations, AKT amplification, PTEN loss, or RTK activation can hyperactivate signaling. It also plays roles in metabolic disorders and insulin signaling. Pharmacological targeting includes PI3K inhibitors, AKT inhibitors, and mTOR inhibitors, though therapeutic resistance and feedback activation pose clinical challenges.

Terminology and scope: The term routes emphasizes the dynamic routing of signals through PI3K and AKT, including tissue- and context-specific variations via PI3K isoforms (p110α, p110β, p110δ, p110γ). Understanding PI3KAKTroutes requires considering upstream receptors, lipid second messengers, AKT isoforms, and downstream metabolic and transcriptional programs that shape cellular fate.