3-phosphoinositide-dependent protein kinase-1 (PDK1) is a central mediator of cellular signaling between phosphoinositide-3
kinase and various intracellular
serine/threonine kinases, including
protein kinase B, p70 ribosomal
S6 kinase, serum and
glucocorticoid-inducible
kinase, and
protein kinase C. PDK1 activates members of the AGC family of
protein kinases by phosphorylating
serine/
threonine residues in the activation loop. Here, we review the regulatory mechanisms of PDK1 and its roles in
cancer. PDK1 is activated by autophosphorylation in the activation loop and other
serine residues, as well as by phosphorylation of Tyr-9 and Tyr-373/376. Src appears to recognize PDK1 following
tyrosine phosphorylation. The role of
heat shock protein 90 in regulating PDK1 stability and PDK1-Src complex formation are also discussed. Furthermore, we summarize the subcellular distribution of PDK1. Finally, an important role for PDK1 in
cancer chemotherapy is proposed. In conclusion, a better understanding of its molecular regulatory mechanisms in various signaling pathways will help to explain how PDK1 acts as an oncogenic
kinase in various
cancers, and will contribute to the development of novel
cancer chemotherapies.