Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling

Abstract

Precise balance between phosphorylation, catalyzed by protein kinases, and dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states that drive diseases such as cancer, heart disease, and diabetes. The recent discovery of the PHLPP (pleckstrin homology domain leucine-rich repeat protein phosphatase) family of Ser/Thr phosphatases adds a new player to the cast of phosphate-controlling enzymes in cell signaling. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis. The frequent deletion of PHLPP in cancer, coupled with the development of prostate tumors in mice lacking PHLPP1, identifies PHLPP as a novel tumor suppressor. This minireview discusses the structure, function, and regulation of PHLPP, with particular focus on its role in disease.

FIGURE 1.

Domain structure of PHLPP. A, domain structure of PHLPP family members showing predicted Ras association domain (RA; purple), PH domain (cyan), LRRs (orange), PP2C domain (yellow), and C-terminal PDZ-binding motif (pink). a.a., amino acids. B, model of the PP2C domain of PHLPP2 showing active site acidic residues (Asp-806, Glu-990, and Asp-1024; pink) that coordinate two Mn²⁺ ions (green spheres) (13). Leu-1016, which is present as Ser in 30% of the population, is highlighted in blue. C, surface rendition of the active site of PHLPP2 docked with a phosphorylated hydrophobic motif peptide from Akt (HFPQFpSYSAS; with phosphorylated Ser (Ser-473) in red and underlined hydrophobic residues in cyan). Active site residues and Mn²⁺ are colored as described for B. The alignment of hydrophobic phosphorylation motif sequences of PKCβII, Akt1, and S6K1 is indicated.

FIGURE 2.

Role of PHLPP in terminating oncogenic signaling pathways. PHLPP (red) directly dephosphorylates and inactivates Akt, PKC, and S6K, thus opposing cell survival and proliferation signals, and directly dephosphorylates and activates Mst1, thus promoting pro-apoptotic signals. Indicated are two negative feedback loops: high Akt activity up-regulates PHLPP levels by suppressing GSK-3-dependent degradation, and high S6K activity up-regulates PHLPP expression. Note that targeting the PI3K pathway within these feedback loops will have the consequence of decreasing PHLPP levels, thus promoting prosurvival pathways mediated by PKC and inhibiting pro-apoptotic pathways mediated by Mst1. Protein kinases are shown in green, and tumor suppressors are shown in red (the lipid phosphatase PTEN, which opposes the lipid kinase PI3K, and the protein phosphatase PHLPP, which controls the indicated protein kinases). RTK, receptor tyrosine kinase.