PDK2: a complex tail in one Akt.
The kinase Akt contains two phosphatidylinositol-3 kinase (PI3K)-dependent phosphorylation sites, one in the activation loop (Thr(308)) and one in the carboxyl-terminal tail (Ser(473)), both of which are conserved among the members of the AGC kinase family. Under physiological conditions, the phosphorylation of Thr(308) appears to be coordinately regulated with the phosphorylation of Ser(473). Under experimental conditions, however, the two sites can be uncoupled, suggesting that their phosphorylation is controlled by different kinases and phosphatases. Phosphoinositide-dependent kinase 1 (PDK1), the kinase that phosphorylates the activation loop site, has been unambiguously identified. However, PDK2, a kinase that is hypothesized to phosphorylate the hydrophobic carboxyl-terminal site, remains elusive. This Perspective examines the regulation and biological significance of Akt phosphorylation at Ser(473). The authors propose that Ser(473) undergoes both autophosphorylation and phosphorylation by other kinases. Both events may be promoted by interactions between PDK1 and phosphorylated or phosphomimetically altered hydrophobic phosphorylation motifs in kinases associated with Akt. These interactions may induce conformational changes in Akt that make Ser(473) accessible to phosphorylation.
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The authors are at the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. P_Tsichlis@lac.jci.tju.edu
Tsichlis
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D064413:3-Phosphoinositide-Dependent Protein Kinases; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt
D011518:Proto-Oncogene Proteins; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt