PDK2: A Complex Tail in One Akt

Science's STKE  23 Jan 2001:
Vol. 2001, Issue 66, pp. pe1
DOI: 10.1126/stke.2001.66.pe1

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The kinase Akt contains two phosphatidylinositol-3 kinase (PI3K)-dependent phosphorylation sites, one in the activation loop (Thr308) and one in the carboxyl-terminal tail (Ser473), both of which are conserved among the members of the AGC kinase family. Under physiological conditions, the phosphorylation of Thr308 appears to be coordinately regulated with the phosphorylation of Ser473. 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 Ser473. The authors propose that Ser473 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 Ser473 accessible to phosphorylation.

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