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).
Organ Systems
endocrine
nervous
cardiovascular
immune-hematologic
musculoskeletal
Pathway Steps
insulin / IGF-1 / RTK-ligand → IRS-1/2 phosphorylation or SH2 of p85 — via receptor autophosphorylation → recruitment of class IA PI3K (p110α/β/δ + p85). Receptor tyrosine kinases recruit class IA PI3K either directly (p85 SH2 domains binding phosphotyrosines) or via IRS-1/2 adaptors (the insulin/IGF route). This is the most frequently activated oncogenic node in cancer — PIK3CA (p110α) is among the commonest mutated oncogenes.
PI3K active → PIP2 → PIP3 at plasma membrane — via opposed by PTEN (PIP3 → PIP2); PTEN loss → constitutive AKT (oncogenesis). PI3K phosphorylates PIP2 to the lipid second messenger PIP3 at the membrane; PTEN is the phosphatase that reverses this and is one of the most commonly lost tumor suppressors. PIP3 is the on-switch — its level, set by the PI3K/PTEN balance, gates everything downstream.
PIP3 → AKT + PDK1 PH-domain recruitment — via membrane co-localization → AKT-Thr308 phosphorylation by PDK1. PIP3 recruits AKT and PDK1 to the membrane via their PH domains, and PDK1 phosphorylates AKT at Thr308. Membrane co-localization is the key activation event, which is why PTEN loss (sustained PIP3) drives constitutive AKT signaling.
AKT-Thr308 + mTORC2 → AKT-Ser473 (fully active AKT) — via mTORC2 (RICTOR) provides the second phospho — distinct from mTORC1. Full AKT activation needs a second phosphorylation at Ser473 by mTORC2 (the rapamycin-insensitive, RICTOR-containing complex) — distinct from mTORC1. So mTOR sits both upstream of AKT (as mTORC2) and downstream (as mTORC1), creating feedback loops that complicate PI3K-pathway drug responses.
AKT active → TSC2 phosphorylation — via → mTORC1 activation → protein synthesis, lipogenesis. AKT phosphorylates and inhibits TSC2, releasing Rheb to switch on mTORC1 → protein synthesis and lipogenesis. mTORC1 then feeds back to suppress IRS-1, so rapalogs can paradoxically relieve this brake and re-activate upstream AKT — an important resistance mechanism.
AKT active → GSK-3β phosphorylation → inhibition — via ↑glycogen synthesis (GS active) + β-catenin stabilization (cross-link to Wnt). AKT phosphorylates and inhibits GSK-3β, which both activates glycogen synthase (insulin’s glycogen-storage effect) and stabilizes β-catenin and other GSK-3 substrates — a node where the insulin/growth-factor and Wnt pathways intersect.
AKT active → FoxO1/3/4 phosphorylation → cytoplasmic sequestration — via ↓gluconeogenesis (FoxO1 in liver) + ↓apoptosis + ↓autophagy genes. AKT phosphorylates FoxO transcription factors, sequestering them in the cytoplasm (14-3-3-bound). In liver this shuts off FoxO1-driven gluconeogenesis (insulin’s glucose-lowering action); broadly it suppresses the FoxO apoptosis, autophagy, and stress-resistance program — a key pro-growth output.
AKT active → BAD / MDM2 / eNOS / p21 phosphorylation — via anti-apoptotic + p53-degrading + vasodilatory + cell-cycle effects. AKT’s pro-survival/growth signature comes from phosphorylating many substrates: BAD (blocks apoptosis), MDM2 (promotes p53 degradation), eNOS (vasodilation), and p21/p27 (cell cycle). This breadth is why constitutive PI3K/AKT activation is so oncogenic and so heavily drug-targeted (PI3K/AKT/mTOR inhibitors).
Known Modulators
insulin (activator) — PI3K via IRS-1/2 (canonical upstream)