PHLiPPing the switch on Akt and protein kinase C signaling

Abstract

The Ser/Thr-specific phosphatase PHLPP [pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase] provides 'the brakes' for Akt and protein kinase C (PKC) signaling. The two isoforms of this recently discovered family, PHLPP1 and PHLPP2, control the amplitude and duration of signaling of Akt and PKC by catalyzing the dephosphorylation of the hydrophobic phosphorylation motif, a C-terminal phosphorylation switch that controls these kinases. Aberrant regulation of either kinase accompanies many diseases, notably diabetes and cancer. By specifically dephosphorylating the hydrophobic motif, PHLPP controls the degree of agonist-evoked signaling by Akt and the cellular levels of PKC. This review focuses on the function of PHLPP1 and PHLPP2 in modulating signaling by Akt and PKC.

Figure 1

Domain composition and phylogeny of PHLPP isoforms A. Domain composition of PHLPP family members showing the Ras association domain (RA; dark blue), pleckstrin homology domain (PH; cyan), Leucine rich repeat (LRR; orange) region, PP2C domain (yellow), and PDZ binding motif (pink). Gray arrow head denotes the splice site for PHLPP1β. B. Phylogenetic tree of PPM phosphatase domains (human) showing PHLPP as a discrete subfamily (highlighted in yellow) of the PP2C class. Sequences were aligned using ClustalW (Gonnet matrix)

Figure 2

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.

Figure 3

Activation of PKC and Akt pathways by lipid second messengers. Model showing activation of PKC and Akt signaling pathways by lipid second messengers (diacylglycerol (DG) for PKC and phosphaticylinositol-3,4,5-trisphosphate (PIP3) for Akt) and phosphorylation catalyzed by PDK-1. Phosphorylation by PDK-1 on the activation loop (pink phosphate) triggers phosphorylation on the hydrophobic motif (green phosphate), an event that depends on functional mTORC2 in the cell. Once phosphorylated, Akt moves throughout the cell phosphorylating substrates. PKC, in contrast, must be bound to diacylglycerol to signal. Signaling is terminated by removal of the second messengers (catalyzed by PTEN and diacylglycerol kinase) and removal of the activating phosphates. PHLPP catalyzes the dephosphorylation of the hydrophobic motif, suppressing the amplitude of signaling by Akt and PKC. For Akt, dephosphorylation of the hydrophobic motif acutely inactivates the kinase. For PKC, this chronically controls the levels of the kinase because the dephosphorylated form is rapidly degraded.