Wiring of PHLPP/Akt pathways
PHLPP1 and PHLPP2 selectively control the phosphorylation state of specific Akt isozymes, which in turn control the phosphorylation of specific substrates. Following mitogen stimulation, Akt is phosphorylated on the activation loop (pink; Thr308 in Akt1) by PDK-1, an event that triggers phosphorylation of the hydrophobic motif by a mechanism that depends on mTORC2 (green; Ser473 in Akt1). Akt1, Akt2, and Akt3 phosphorylate both isoform-specific (HDM2, p27) and shared (GSK-3β) substrates. Specific interactions (light blue ovals) of PHLPP1 or PHLPP2 with Akt1, Akt2, or Akt3 allow PHLPP isoforms to differentially control the amplitude of Akt signaling towards downstream substrates. Adapted from [11] with permission.