PI3KAKTWeg

PI3KAKTWeg, commonly understood as the PI3K/AKT pathway, is a conserved signal transduction cascade that integrates growth factor signals to control cell growth, survival, metabolism and proliferation. The pathway is driven primarily by class I phosphoinositide 3-kinases (PI3Ks), which include catalytic subunits p110α, p110β, p110δ and p110γ paired with regulatory subunits such as p85. Activation occurs when extracellular cues through receptor tyrosine kinases or G protein–coupled receptors stimulate PI3K to convert the membrane lipid PIP2 to PIP3.

Formation of PIP3 at the inner leaflet recruits PH-domain–containing proteins, including AKT and PDK1. PDK1 phosphorylates AKT at Thr308, while mTOR complex 2 phosphorylates AKT at Ser473, yielding full kinase activation. Active AKT then phosphorylates diverse substrates to promote protein synthesis and growth, while inhibiting apoptosis and modulating metabolism. Major downstream targets include inhibition of the TSC1/2 complex leading to mTORC1 activation, and phosphorylation of FOXO transcription factors, GSK3 and BAD, among others.

Negative regulation tightly controls the pathway. PTEN dephosphorylates PIP3 to PIP2, reducing membrane recruitment of AKT, while other phosphatases such as SHIP1/2 contribute by converting PIP3 to PI(3,4)P2. Loss or mutation of pathway components, especially PIK3CA (p110α) or PTEN, is common in cancer and can promote uncontrolled growth and resistance to therapy. The pathway also participates in insulin signaling and metabolic regulation.

Therapeutic inhibition targets include PI3K inhibitors (pan-PI3K or isoform-specific) and AKT or mTOR inhibitors; examples used in oncology include alpelisib (PI3Kα-specific) and idelalisib (PI3Kδ-specific). Continued research aims to clarify context-specific roles and overcome resistance mechanisms.