| Phosphoinositide-dependent kinase 1 (PDK1) is a serine/threonine kinase of the AGC family encoded by PDPK1, acting as a master regulator transducing PI3K signals from growth factors like insulin to activate over 20 AGC kinases, including Akt, S6K, RSK, SGK, and PKC isoforms, crucial for cell survival, proliferation, metabolism, and migration. PDK1 features an N-terminal kinase domain with constitutively autophosphorylated Ser241 in the activation loop and a PIF-pocket (Gln150, Thr148, Ile119) for hydrophobic motif docking on substrates, as well as a C-terminal pleckstrin homology (PH) domain (Arg472, Arg474, Lys465) that binds PIP3/PI(3,4)P2, recruiting PDK1 to the plasma membrane. There, phosphoinositide engagement relieves cytosolic autoinhibition, promotes side-to-side dimerization, and enables high-affinity phosphorylation of activation loops (e.g., Akt Thr308, S6K Thr389) through coordinated alignment of ATP and substrate in the active site. This amplifies PI3K/Akt/mTOR signaling for protein synthesis (via 4E-BP1/S6K), glucose uptake (via AS160), anti-apoptosis (via Bad/FoxO), and cytoskeletal remodeling (via PKC/Rho), while regulating PDH phosphorylation for Warburg-like metabolic reprogramming in cancer. PDK1 is essential for development, as shown by embryonic lethality in knockout mice, and its overexpression or hyperactivation in breast, lung, and prostate cancers is linked to poor prognosis and metastasis through unchecked PI3K signaling. |