mTOR

mTOR is activated downstream of growth factor receptor signaling via PI3K-AKT, as well as by amino acid availability (especially leucine) and cellular energy status (sensed via AMPK, which inhibits mTORC1 when ATP is low). mTORC1 promotes anabolic processes: protein synthesis (via phosphorylation of S6K1 and 4E-BP1, promoting cap-dependent translation), lipid synthesis, and ribosome biogenesis, while inhibiting autophagy. mTORC2 regulates cytoskeletal organization and further activates AKT via phosphorylation at Ser473, forming a feedback loop. Dysregulated mTOR signaling (often due to loss of tumor suppressors like PTEN, TSC1/TSC2, or LKB1) is implicated in cancer, tuberous sclerosis complex (TSC1/2 mutations lead to hamartomas, renal angiomyolipomas, and lymphangioleiomyomatosis), and metabolic syndrome. Clinically, mTOR inhibitors—sirolimus (rapamycin), everolimus, and temsirolimus—are used as immunosuppressants in solid organ transplantation (prevent T-cell proliferation by blocking IL-2 signal transduction), in drug-eluting coronary stents to prevent restenosis, and as targeted cancer therapy (e.g., renal cell carcinoma, subependymal giant cell astrocytomas in TSC). Side effects include hyperlipidemia, impaired wound healing, myelosuppression, and increased infection risk, but notably sirolimus is not nephrotoxic, unlike calcineurin inhibitors (cyclosporine, tacrolimus). Understanding mTOR's role in the TSC1/TSC2-Rheb-mTORC1 axis is high-yield for USMLE Step 1, linking molecular biology to tuberous sclerosis pathology and pharmacologic immunosuppression.