Category: signaling
PI3K → AKT is the central insulin / growth factor transduction axis — distinct from [[mtor_signaling]] (which it feeds into) by encompassing the upstream RTK→PI3K activation and the broader AKT effector set (FoxO, GSK-3β, BAD, eNOS, p21, p27, MDM2). Class IA PI3K (p110α/β/δ + p85 regulatory subunit) recruited to phospho-tyrosine motifs (IRS-1 for insulin; SH2 of p85 for RTK-direct) → catalyzes PIP2 → PIP3 at plasma membrane → PIP3 recruits PDK1 + AKT (via PH domain) → AKT-Thr308 (PDK1) + AKT-Ser473 (mTORC2) → fully active AKT. AKT phosphorylates a wide effector set: TSC2 (→ mTORC1 activation), GSK-3β (inhibition → ↑glycogen synthesis + β-catenin stabilization — cross-link [[wnt_beta_catenin]]), FoxO1/3/4 (cytoplasmic sequestration → ↓gluconeogenesis + ↓apoptosis), BAD (anti-apoptotic), eNOS (vasodilation), p21/p27 (cell cycle), MDM2 (p53 turnover). PTEN dephosphorylates PIP3 → PIP2 → tumor suppressor (loss → constitutive AKT). Insulin signaling specificity: IRS-1/2 → PI3K p110α dominant; deletion causes insulin resistance. Therapeutic relevance: PI3Kα inhibitors (alpelisib for PIK3CA-mutant breast cancer); PI3Kδ (idelalisib — CLL); mTOR inhibitors (rapamycin) block downstream; metformin/AMPK opposes via TSC2. Cross-links: [[mtor_signaling]] (downstream), [[insulin_glucose_homeostasis]] (insulin → IRS → PI3K), [[wnt_beta_catenin]] (GSK-3β shared node).