P70-S6 Kinase 1

Phosphorylation

Kinase

Chemistry

Ribosomal s6 kinase

Proto-Oncogene Proteins c-akt

Signal transduction

Protein kinase B

PI3K/AKT/mTOR pathway

Biology

Cell biology

mTORC1

Nature Communications

Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers. The direct upstream regulation of PDK1 is not fully understood. Here the authors demonstrate that S6K1 directly phosphorylates PDK1 to inhibit AKT kinase activity and its ability to drive tumourigenesis.

S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions