Pi3k akt mtor pathway · HTML
PI3K–AKT–mTOR is the metabolic engine of the T-cell response. Antigen engagement of the TCR/CD3 complex together with co-stimulation through CD28, ICOS or 4-1BB recruits PI3K p110δ/p85 to the membrane, converting PIP2 to PIP3 and docking PDK1 and AKT; mTORC2 (RICTOR) completes AKT activation. AKT then releases the brakes on growth — inactivating TSC1/TSC2 to free RHEB and switch on mTORC1, while phosphorylating FOXO1/FOXO3, GSK3β, PRAS40 and BAD. mTORC1 drives S6K1/RPS6 and relieves 4E-BP1 from eIF4E, translating HIF-1α, MYC, SREBP1 and IRF4 to install aerobic glycolysis (GLUT1, HK2, LDHA) and glutaminolysis (GLS) — the effector programme. Opposing it, the phosphatases PTEN, SHIP1, PHLPP1 and PP2A, the PD-1/CTLA-4–SHP-2 checkpoint axis and the LKB1–AMPK energy-stress arm restrain the pathway, favouring FOXO/TCF-1-dependent quiescence, fatty-acid oxidation (PGC-1α, CPT1A) and memory — or, when signalling is chronically distorted, exhaustion. Click any protein for the matching Assay Genie In Vivo antibody or ELISA kit.
Input and lipid switch. TCR/CD3 ligation activates LCK (held in check by CSK) and ZAP70, building the LAT–GRB2 scaffold. CD28, ICOS and 4-1BB recruit the p85 regulatory subunit and its catalytic partner p110δ, the lymphocyte-restricted class IA PI3K. p110δ phosphorylates PIP2 to PIP3, creating the membrane docking site for the PH domains of PDK1 and AKT. The lipid signal is erased by two phosphatases — PTEN (3-phosphatase) and SHIP1 (5-phosphatase) — while PD-1 and CTLA-4 recruit SHP-2 to dephosphorylate the CD28/PI3K module. This is why checkpoint blockade is, mechanistically, a way of restoring PI3K–AKT flux.
AKT and the mTORC1 switch. PDK1 phosphorylates AKT at T308 and mTORC2 (RICTOR) at S473; PHLPP1 and PP2A reverse both. Active AKT is a brake-release enzyme: it inactivates the TSC1/TSC2 GAP complex so that GTP-loaded RHEB accumulates and switches on mTORC1 (mTOR, RAPTOR, mLST8, restrained by DEPTOR and PRAS40); it inhibits GSK3β and BAD; and it phosphorylates FOXO1/FOXO3, evicting them from the nucleus. mTORC1 also integrates nutrients — leucine and glutamine imported by LAT1 signal through the RagA/B GTPases — and energy status, via LKB1–AMPK and Sestrin 2, which inhibit mTORC1 and activate ULK1-dependent autophagy.
Output: two opposing T-cell fates. mTORC1 phosphorylates S6K1 (then RPS6) and releases 4E-BP1 from eIF4E, licensing cap-dependent translation of HIF-1α, MYC, SREBP1, IRF4 and T-bet. These install the effector programme: GLUT1-driven glucose uptake, HK2 and LDHA aerobic glycolysis, GLS glutaminolysis, clonal expansion and cytokine output. When the pathway is dampened — by checkpoints, PTEN, AMPK or nutrient restriction — nuclear FOXO1 sustains TCF-1 and EOMES, PGC-1α and CPT1A shift cells to fatty-acid oxidation, and quiescent memory differentiation is favoured; chronic, distorted signalling with nuclear NFAT instead drives exhaustion. Assay Genie In Vivo low-endotoxin antibodies let you perturb every receptor at the top of this map in mice, and the ELISA kits quantify the phospho-nodes and metabolic enzymes downstream. For research use only; not for diagnostic or therapeutic procedures.
Every protein node links to a product — In Vivo antibody, ELISA kit or research antibody.