Multiple implications of 3-phosphoinositide-dependent protein kinase 1 in human cancer

Abstract

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.

Keywords: 3-phosphoinositide-dependent protein kinase-1; Cancer therapy; Cell signaling; Oncogenic kinase; Protein kinase B.

Figure 1

Secondary structure and phosphorylation sites of 3-phosphoinositide-dependent protein kinase-1. A: 3-phosphoinositide-dependent protein kinase-1 (PDK1) consists of an N-terminal kinase catalytic domain (CD; amino acids 71-359) and a C-terminal pleckstrin homology (PH) domain (amino acids 459-550). The nuclear export sequence (NES) (amino acids 379-388) is essential for exporting PDK1 into the cytoplasm from the nucleus. The phosphorylation sites of PDK1 include Ser-241 and Tyr-373/376, which is dependent on Tyr-9 and required for PDK1 catalytic activity; B: Crystal structure of the human PDK1 kinase domain. Residues 71-163 are green (small lobe) and residues 164-358 are blue (large lobe). The αC-helix (amino acids 124-136) is boxed in black and encompasses residues 287-295, which are purple. The hydrophobic motif (HM) pocket with the Ser-241 in the activation loop is also shown. This figure was adopted from Biondi et al[26], 2002.

Figure 2

Proposed mechanism for the regulation of 3-phosphoinositide-dependent protein kinase-1 phosphorylation and stability. 3-phosphoinositide-dependent protein kinase-1 (PDK1) autophosphorylates itself on Ser-241. In the presence of pervanadate or insulin, PDK1 is phosphorylated on Tyr-9 and Tyr-373/376 with the help of Src and heat shock protein 90 (Hsp90). Tyrosine phosphorylation further increases PDK1 catalytic activity. In the absence of Hsp90 interaction, PDK1 is promoted towards proteasome-dependent degradation. This figure was adopted from Yang et al[41], 2008. PI3K: Phosphoinositide 3-kinase; PI(4,5)P₂: Phosphatidylinositol 3,4 bisphosphate; PI(3,4,5)P₃: Phosphatidylinositol 3,4,5 trisphosphate; CA: Constitutively active; PH: Pleckstrin homology; PKB: Protein kinase B; SGK: Serum and glucocorticoid-inducible kinase.

Figure 3

Regulation of 3-phosphoinositide-dependent protein kinase-1 cellular localization. A: 3-phosphoinositide-dependent protein kinase-1 (PDK1) resides in the cytoplasm and membranes in unstimulated cells, and can shuttle between these two compartments. The treatment of cells with leptomycin-B results in PDK1 accumulation in the nucleus. The localization of this kinase to the plasma membrane is disrupted by caveolin-1; B: PDK1 can translocate to the plasma membrane following treatment with pervanadate or insulin, which leads to PDK1 phosphorylation on Tyr-9 and Tyr-373/376; C: Nucleus-cytoplasm shuttle. (1) Phosphoinositide 3-kinase (PI3K) signaling regulates PDK1 nuclear translocation; (2) Insulin growth factor-1 (IGF-1) induces Ser-396 phosphorylation, thereby placing the serine-rich motif (amino acids Ser-389-396) close to its nuclear export sequence (NES) region, which leads to PDK1 nuclear translocation; and (3) Tyrosine phosphatase SH2 domain-1 (SHP-1) binds to PDK1 following tyrosine phosphorylation. The SHP-1/PDK1 complex is recruited to the nuclear membrane by binding to perinuclear phosphatidylinositol 3,4,5 trisphosphate, where SHP-1 and its nuclear localization signal (NLS) facilitates active import. In addition, Src promotes the association of SHP-1 to PDK1. Nuclear PDK1 regulates its nuclear substrates and activates corresponding signaling pathways. PTEN: Phosphatase and tensin homolog; CA: Constitutively active; PH: Pleckstrin homology; PKB: Protein kinase B; SGK: Serum and glucocorticoid-inducible kinase; Hsp90: Heat shock protein 90.