Fig. 7: Models depicting the negative regulation of PDK1 by S6K1 under physiological and pathological conditions.
From: S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
a The canonical activation of PI3K-AKT-mTOR pathway toward growth factors, such as Insulin or EGF treatment. b The negative feedback regulations of AKT kinase by S6K1-mediated phosphorylation of SIN1, PDK1 as well as IRS1. Among which, phosphorylation of IRS1 decreases PI3K-mediated PIP3 generation; phosphorylation of SIN1 dissociates mTORC2 from membrane location; phosphorylation of PDK1 recruits 14-3-3 and dissociates from membrane location. These pathways together tightly negatively control growth factors-induced constant activation of AKT kinase. c Patient-associated PDK1 mutations could block S6K-mediated PDK1 phosphorylation (Type I mutations) or 14-3-3-mediated PDK1 membrane dissociation (Type II mutations), leading to AKT constitutive activation and oncogenic roles, such as accelerating cell proliferation and anti-apoptosis. Red and black arrows indicate positive and negative regulation, respectively. Solid and dotted lines indicate direct and indirect (multistep) regulation, respectively.
